Anthranilamide arthropodicide treatment

ABSTRACT

This invention pertains to methods for protecting a propagule or a plant grown therefrom from invertebrate pests comprising contacting the propagule or the locus of the propagule with a biologically effective amount of a compound of Formula I: its N-oxide or an agriculturally suitable salt thereof wherein A and B and R 1  through R 8  are as defined in the disclosure. This invention also relates to propagules treated with a compound of Formula I and compositions comprising a Formula I compound for coating propagules.

FIELD OF THE INVENTION

[0001] This invention relates to the control of phytophagousinvertebrate pests such as arthropod pests by contacting plantpropagules or the locus of the propagules with certain anthranilamidesand to propagule-coating compositions comprising the anthranilamides.

BACKGROUND OF THE INVENTION

[0002] The control of invertebrate pests such as arthropods is extremelyimportant in achieving high crop efficiency. Damage by invertebratepests to growing and stored agronomic crops can cause significantreduction in productivity and thereby result in increased costs to theconsumer. The control of invertebrate pests in forestry, greenhousecrops, ornamentals and nursery crops is also important.

[0003] Plants are subject to injury by invertebrate pests at all stagesof growth, beginning with seeds or other propagules such as bulbs,tubers, rhizomes, corms, and stem and leaf cuttings and ending withmature plants. Besides the cost of materials, the effort and timerequired for application of invertebrate pest control substances makerepetition of treatments undesirable. Ideally a single treatment of aplant at the propagule stage would protect the plant from invertebratepests during its entire life.

[0004] A variety of techniques for treating propagules with plantprotection substances are known. These include soaking propagules inarthropodicide-comprising solutions, coating propagules with films,pelleting materials and the like comprising arthropodicidalcompositions, and applying arthropodicidal compounds to the growingmedium surrounding the propagules. While some compounds can effectivelyprotect propagules from certain phytophagous invertebrate pests, newcompounds are needed that are more effective or have a broader spectrumof activity, are less costly, less toxic, environmentally safer or havedifferent modes of action.

[0005] Particularly needed are invertebrate pest control treatments thatcan protect the plant not only at its propagule stage but also later inits development. Achieving this objective requires compounds that areactive against invertebrate pests and can effectively translocate fromthe locus of the propagule up through the growing stems, leaves andother aboveground plant parts. Furthermore the compounds need to havehigh activity against invertebrate pests to compensate for the dilutionoccasioned by the expanding plant mass. Also, the compounds cannotrapidly degrade and lose their biological potency in the environment ofthe plant's vascular tissues. The combination of these properties israre. Treatments of propagules effective for protecting fromphytophagous invertebrate pests not only the propagule but also theplant at later growth stages have now been discovered.

SUMMARY OF THE INVENTION

[0006] This invention involves compounds of Formula I, their N-oxidesand their agriculturally suitable salts

[0007] wherein

[0008] A and B are independently O or S;

[0009] R¹ is H, C₁-C₆ alkyl, C₂-C₆ alkoxycarbonyl or C₂-C₆alkylcarbonyl;

[0010] R² is H or C₁-C₆ alkyl;

[0011] R³ is H; C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₃-C₆cycloalkyl, each optionally substituted with one or more substituentsselected from the group consisting of halogen, CN, NO₂, hydroxy, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆alkylcarbonyl, C₃-C₆ trialkylsilyl, phenyl, phenoxy, 5-memberedheteroaromatic rings, and 6-membered heteroaromatic rings;

[0012] each phenyl, phenoxy, 5-membered heteroaromatic ring, and6-membered heteroaromatic ring optionally substituted with one to threesubstituents independently selected from the group consisting of C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkylC₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN,NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈ (alkyl)(cycloalkyl)amino,C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,C₃-C₈ dialkylaminocarbonyl and C₃-C₆ trialkylsilyl; C₁-C₄ alkoxy; C₁-C₄alkylamino; C₂-C₈ dialkylamino; C₃-C₆ cycloalkylamino; C₂-C₆alkoxycarbonyl or C₂-C₆ alkylcarbonyl;

[0013] R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₁-C₆ haloalkyl, CN, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxyor NO₂;

[0014] R⁵ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxyalkyl, C₁-C₄hydroxyalkyl, C(O)R¹⁰, CO₂R¹⁰, C(O)NR¹⁰R¹¹, halogen, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, NR¹⁰R¹¹, N(R¹¹)C(O)R¹⁰, N(R¹¹)CO₂R¹⁰ or S(O)_(n)R¹²;

[0015] R⁶ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, CN, C₁-C₄ alkoxyor C₁-C₄ haloalkoxy;

[0016] R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl orC₃-C₆ halocycloalkyl; or

[0017] R⁷ is a phenyl ring, a benzyl ring, a 5- or 6-memberedheteroaromatic ring, a naphthyl ring system or an aromatic 8-, 9- or10-membered fused heterobicyclic ring system, each ring or ring systemoptionally substituted with one to three substituents independentlyselected from R⁹;

[0018] R⁸ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, C₁-C₄ alkoxy orC₁-C₄ haloalkoxy;

[0019] each R⁹ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈(alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl,C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl or C₃-C₆trialkylsilyl;

[0020] R¹⁰ is H, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

[0021] R¹¹ is H or C₁-C₄ alkyl;

[0022] R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; and

[0023] n is 0, 1 or 2.

[0024] This invention provides a method for protecting a propagule or aplant grown therefrom from an invertebrate pest. The method comprisescontacting the propagule or the locus of the propagule with abiologically effective amount of a compound of Formula I, an N-oxidethereof or an agriculturally suitable salt thereof.

[0025] This invention also provides a propagule comprising abiologically effective amount of a compound of Formula I, its N-oxide oran agriculturally suitable salt thereof.

[0026] This invention further provides a propagule contacted with abiologically effective amount of a compound of Formula I, its N-oxide oran agriculturally suitable salt thereof.

[0027] This invention still further provides an invertebrate pestcontrol composition for coating a propagule comprising a biologicallyeffective amount of a compound of Formula I, its N-oxide or anagriculturally suitable salt thereof and a film former or adhesiveagent.

DETAILED DESCRIPTION OF THE INVENTION

[0028] As referred to in the present disclosure and claims, the term“propagule” means a seed or a regenerable plant part. The term“regenerable plant part” means a part of a plant other than a seed fromwhich a whole plant may be grown or regenerated when the plant part isplaced in horticultural or agricultural growing media such as moistenedsoil, peat moss, sand, vermiculite, perlite, rock wool, fiberglass,coconut husk fiber, tree fern fiber and the like, or even a completelyliquid medium such as water. Regenerable plant parts commonly includerhizomes, tubers, bulbs and corms of such geophytic plant species aspotato, sweet potato, yam, onion, dahlia, tulip, narcissus, etc.Regenerable plant parts include plant parts that are divided (e.g., cut)to preserve their ability to grow into a new plant. Thereforeregenerable plant parts include viable divisions of rhizomes, tubers,bulbs and corms which retain meristematic tissue, such as an eye.Regenerable plant parts can also include other plant parts such as cutor separated stems and leaves from which some species of plants can begrown using horticultural or agricultural growing media. As referred toin the present disclosure and claims, unless otherwise indicated, theterm “seed” includes both unsprouted seeds and sprouted seeds in whichthe testa (seed coat) still surrounds part of the emerging shoot androot.

[0029] In the above recitations, the term “alkyl”, used either alone orin compound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl, pentyl or hexyl isomers. “Alkenyl”includes straight-chain or branched alkenes such as 1-propenyl,2-propenyl, and the different butenyl, pentenyl and hexenyl isomers.“Alkenyl” also includes polyenes such as 1,2-propadienyl and2,4-hexadienyl. “Alkynyl” includes straight-chain or branched alkynessuch as 1-propynyl, 2-propynyl and the different butynyl, pentynyl andhexynyl isomers. “Alkynyl” can also include moieties comprised ofmultiple triple bonds such as 2,5-hexadiynyl. “Alkoxy” includes, forexample, methoxy, ethoxy, n-propyloxy, isopropyloxy and the differentbutoxy, pentoxy and hexyloxy isomers. “Alkoxyalkyl” denotes alkoxysubstitution on alkyl. Examples of “alkoxyalkyl” include CH₃OCH₂,CH₃OCH₂CH₂, CH₃CH₂OCH₂, CH₃CH₂CH₂CH₂OCH₂ and CH₃CH₂OCH₂CH₂.“Alkylthio”includes branched or straight-chain alkylthio moieties suchas methylthio, ethylthio, and the different propylthio, butylthio,pentylthio and hexylthio isomers. “Cycloalkyl” includes, for example,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0030] The term “heterocyclic ring” or “heterocyclic ring system”denotes rings or ring systems in which at least one ring atom is notcarbon and comprises 1 to 4 heteroatoms independently selected from thegroup consisting of nitrogen, oxygen and sulfur, provided that eachheterocyclic ring comprises no more than 4 nitrogens, no more than 2oxygens and no more than 2 sulfurs. The heterocyclic ring can beattached through any available carbon or nitrogen by replacement ofhydrogen on said carbon or nitrogen. The term “aromatic ring system”denotes fully unsaturated carbocycles and heterocycles in which at leastone ring of the polycyclic ring system is aromatic (where aromaticindicates that the Hückel rule is satisfied for the ring system). Theterm “heteroaromatic ring” denotes fully aromatic rings in which atleast one ring atom is not carbon and comprises 1 to 4 heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur, provided that each heterocyclic ring comprises no more than 4nitrogens, no more than 2 oxygens and no more than 2 sulfurs (wherearomatic indicates that the Hückel rule is satisfied). The heterocyclicring can be attached through any available carbon or nitrogen byreplacement of hydrogen on said carbon or nitrogen. The term “aromaticheterocyclic ring system” includes fully aromatic heterocycles andheterocycles in which at least one ring of a polycyclic ring system isaromatic (where aromatic indicates that the Hückel rule is satisfied).The term “fused heterobicyclic ring system” includes a ring systemcomprised of two fused rings in which at least one ring atom is notcarbon and can be aromatic or non aromatic, as defined above.

[0031] The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ andCF₃CCl₂. The terms “haloalkenyl”, “haloalkynyl”, “haloalkoxy”, and thelike, are defined analogously to the term “haloalkyl”. Examples of“haloalkenyl” include (Cl)₂C═CHCH₂ and CF₃CH₂CH═CHCH₂. Examples of“haloalkynyl” include HC≡CCHCl, CF₃C≡C, CCl₃C≡C and FCH₂C≡CCH₂. Examplesof “halo alkoxy” include CF₃O, CCl₃CH₂O, HCF₂CH₂CH₂O and CF₃CH₂O.

[0032] The total number of carbon atoms in a substituent group isindicated by the “C_(i)-C_(j)” prefix where i and j are numbers from 1to 8. For example, C₁-C₄ alkylsulfonyl designates methylsulfonyl throughbutylsulfonyl; C₂ alkoxyalkyl designates CH₃OCH₂; C₃ alkoxyalkyldesignates, for example, CH₃CH(OCH₃), CH₃OCH₂CH₂ or CH₃CH₂OCH₂; and C₄alkoxyalkyl designates the various isomers of an alkyl group substitutedwith an alkoxy group containing a total of four carbon atoms, examplesincluding CH₃CH₂CH₂OCH₂ and CH₃CH₂OCH₂CH₂. In the above recitations,when a compound of Formula I comprises a heterocyclic ring, allsubstituents are attached to this ring through any available carbon ornitrogen by replacement of a hydrogen on said carbon or nitrogen.

[0033] When a group has a substituent which can be hydrogen, for exampleR³, then, when this substituent is taken as hydrogen, it is recognizedthat this is equivalent to said group being unsubstituted.

[0034] Compounds of Formula I can exist as one or more stereoisomers.The various stereoisomers include enantiomers, diastereomers,atropisomers and geometric isomers. One skilled in the art willappreciate that one stereoisomer may be more active and/or may exhibitbeneficial effects when enriched relative to the other stereoisomer(s)or when separated from the other stereoisomer(s). Additionally, theskilled artisan knows how to separate, enrich, and/or to selectivelyprepare said stereoisomers. Accordingly, the compounds of the inventionmay be present as a mixture of stereoisomers, individual stereoisomers,or as an optically active form.

[0035] The salts of compounds of Formula I include acid-addition saltswith inorganic or organic acids such as hydrobromic, hydrochloric,nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic,malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic orvaleric acids.

[0036] Methods, propagules and compositions of the invention preferredfor reason of cost, ease of chemical synthesis or application, and/orbiological efficacy involve the following preferred compounds:

[0037] Preferred 1. A compound of Formula I wherein

[0038] A and B are both O;

[0039] R⁷ is a phenyl ring or a 5- or 6-membered heteroaromatic ringselected from the group consisting of

[0040] each ring optionally substituted with one to three substituentsindependently selected from R⁹;

[0041] Q is O, S, NH or NR⁹; and

[0042] W, X, Y and Z are independently N, CH or CR⁹, provided that inJ-3 and J-4 at least one of W, X, Y or Z is N.

[0043] Preferred 2. A compound of Preferred 1 wherein

[0044] R¹, R² and R⁸ are all H;

[0045] R³ is C₁-C₄ alkyl optionally substituted with halogen, CN, OCH₃or S(O)_(p)CH₃;

[0046] R⁴ group is attached at position 2;

[0047] R⁴ is CH₃, CF₃, OCF₃, OCHF₂, CN or halogen;

[0048] R⁵ is H, CH₃ or halogen;

[0049] R⁶ is CH₃, CF₃ or halogen;

[0050] R⁷ is phenyl or 2-pyridinyl, each optionally substituted; and pis 0, 1 or 2.

[0051] Preferred 3. A compound of Preferred 2 wherein R³ is C₁-C₄ alkyland R⁶ is CF₃.

[0052] Preferred 4. A compound of Preferred 2 wherein R³ is C₁-C₄ alkyland R⁶ is Cl or Br.

[0053] As noted above, R⁷ is (among others) a phenyl, a benzyl, a 5- or6-membered heteroaromatic ring, a naphthyl ring system or an aromatic8-, 9- or 10-membered fused heterobicyclic ring system, each ring orring system optionally substituted with one to three substituentsindependently selected from R⁹. The term “optionally substituted” inconnection with these R⁷ groups refers to groups which are unsubstitutedor have at least one non-hydrogen substituent that does not extinguishthe invertebrate pest control activity possessed by the unsubstitutedanalog. Note also that J-1 through J-4 below denote 5- or 6-memberedheteroaromatic rings. An example of a phenyl ring optionally substitutedwith 1 to 3 R⁹ is the ring illustrated as J-5 in Exhibit 1, wherein r isan integer from 0 to 3. An example of a benzyl ring optionallysubstituted with 1 to 3 R⁹ is the ring illustrated as J-6 in Exhibit 1,wherein r is an integer from 0 to 3. An example of a naphthyl ringsystem optionally substituted with 1 to 3 R⁹ is illustrated as J-59 inExhibit 1, wherein r is an integer from 0 to 3. Examples of a 5- or6-membered heteroaromatic ring optionally substituted with 1 to 3 R⁹include the rings J-7 through J-58 illustrated in Exhibit 1 wherein r isan integer from 0 to 3. Note that J-7 through J-26 are examples of J-1,J-27 through J-41 are examples of J-2, and J-46 through J-58 areexamples of J-3 and J-4. The nitrogen atoms that require substitution tofill their valence are substituted with H or R⁹. Note that some J groupscan only be substituted with less than 3 R⁹ groups (e.g. J-19, J-20,J-23 through J-26 and J-37 through J40 can only be substituted with oneR⁹). Examples of aromatic 3-, 9- or 10-membered fused heterobicyclicring systems optionally substituted with 1 to 3 R⁹ include J-60 throughJ-90 illustrated in Exhibit I wherein r is an integer from 0 to 3.Although R⁹ groups are shown in the structures J-5 through J-90, it isnoted that they do not need to be present since they are optionalsubstituents. Note that when the attachment point between (R⁹)_(r) andthe J group is illustrated as floating, (R⁹)_(r) can be attached to anyavailable carbon atom of the J group. Note that when the attachmentpoint on the J group is illustrated as floating, the J group can beattached to the remainder of Formula I through any available carbon ofthe J group by replacement of a hydrogen atom.

[0054] One or more of the following methods and variations as describedin Schemes 1-22 can be used to prepare the compounds of Formula I. Thedefinitions of A, B and R¹ through R⁹ in the compounds of Formulae 240below are as defined above in the Summary of the Invention unlessindicated otherwise. Compounds of Formulae Ia-d, 2a-d, 3a, 4a-d, 5a-b,17a-c, 18a and 32a-b are various subsets of the compounds of Formula I,2, 3, 4, 5, 17, 18 and 32. In the schemes, Het is the moiety shownbelow:

[0055] A typical method for preparation of a compound of Formula Ia isdescribed in Scheme 1.

[0056] The method of Scheme 1 involves coupling of an amine of Formula 2with an acid chloride of Formula 3 in the presence of an acid scavengerto provide the compound of Formula Ia. Typical acid scavengers includeamine bases such as triethylamine, N,N-diisopropylethylamine andpyridine; other scavengers include hydroxides such as sodium andpotassium hydroxide and carbonates such as sodium carbonate andpotassium carbonate. In certain instances it is useful to usepolymer-supported acid scavengers such as polymer-bound[,N-diisopropylethylamine and polymer-bound 4-(dimethylamino)pyridine.The coupling can be run in a suitable inert solvent such astetrahydrofuran, dioxane, diethylether or dichloromethane to afford theanilide of Formula Ia.

[0057] A thioamide of Formula Ib can be obtained in a subsequent stepfrom the corresponding amide of Formula Ia by treatment with one of avariety of standard thio transfer reagents including phosphoruspentasulfide and Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4disulfide).

[0058] As shown in Scheme 2, an alternate procedure for the preparationof compounds of Formula Ia involves coupling of an amine of Formula 2with an acid of Formula 4 in the presence of a dehydrating agent such asdicyclohexylcarbodiimide (DCC), 1,1′-carbonyl-diimidazole,bis(2-oxo-3-oxazolidinyl)phosphinic chloride orbenzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate.

[0059] Polymer-supported reagents are again useful here, such aspolymer-bound cyclohexylcarbodiimide. The coupling can be run in asuitable inert solvent such as dichloromethane or N,N-dimethylformamide.The synthetic methods of Schemes 1 and 2 are just representativeexamples of a wide variety of coupling methods useful for thepreparation of Formula I compounds; the synthetic literature isextensive for this type of coupling reaction.

[0060] One skilled in the art will also realize that acid chlorides ofFormula 3 may be prepared from acids of Formula 4 by numerous well-knownmethods. For example, acid chlorides of Formula 3 are readily made fromcarboxylic acids of Formula 4 by reacting the carboxylic acid 4 withthionyl chloride or oxalyl chloride in an inert solvent such as tolueneor dichloromethane in the presence of a catalytic amount ofN,N-dimethylformamide.

[0061] As shown in Scheme 3, amines of Formula 2a are typicallyavailable from the corresponding 2-nitrobenzamides of Formula 5 viacatalytic hydrogenation of the nitro group.

[0062] Typical procedures involve reduction with hydrogen in thepresence of a metal catalyst such as palladium on carbon or platinumoxide and in hydroxylic solvents such as ethanol and isopropanol. Aminesof Formula 2a can also be prepared by reduction with zinc in aceticacid. These procedures are well documented in the chemical literature.R¹ substituents such as C₁-C₆ alkyl can be introduced at this stagethrough well known methodologies including either direct alkylation orthrough the generally preferred method of reductive alkylation of theamine. As is further shown in Scheme 3, a commonly employed procedure isto combine the amine 2a with an aldehyde in the presence of a reducingagent such as sodium cyanoborohydride to produce the Formula 2bcompounds where R¹ is C₁-C₆ alkyl.

[0063] Scheme 4 shows that compounds of Formula Ic can be alkylated oracylated with a suitable alkylating or acylating agent such as an alkylhalide, alkyl chloroformate or acyl chloride in the presence of a basesuch as sodium hydride or n-butyllithium in an inert solvent such astetrahydrofuran or N,N-dimethylformamide to afford anilides of FormulaId wherein R¹ is other than hydrogen.

[0064] The intermediate amides of Formula 5a are readily prepared fromcommercially available 2-nitrobenzoic acids. Typical methods for amideformation can be used. As shown in Scheme 5, these methods includedirect dehydrative coupling of acids of Formula 6 with amines of Formula7 using for example DCC, and conversion of the acids to activated formssuch as the acid chlorides or anhydrides and subsequent coupling withamines to form amides of Formula 5a.

[0065] Alkyl chloroformates, such as ethyl chloroformate or isopropylchloroformate, are especially useful reagents for this type of reactioninvolving activation of the acid. The chemical literature is extensiveregarding methods for amide formation. Amides of Formula 5a are readilyconverted to thioamides of Formula 5b by using commercially availablethio transfer reagents such as phosphorus pentasulfide and Lawesson'sreagent.

[0066] Intermediate anthranilic amides of Formula 2c or 2d may also beprepared from isatoic anhydrides of Formula 8 or 9, respectively, asshown in Scheme 6.

[0067] Typical procedures involve combination of equimolar amounts ofthe amine 7 with the isatoic anhydride in polar aprotic solvents such aspyridine and N,N-dimethylformamide at temperatures ranging from roomtemperature to 100° C. R¹ substituents such as alkyl and substitutedalkyl may be introduced by the base-catalyzed alkylation of isatoicanhydride 8 with known alkylating reagents R¹-Lg (wherein Lg is anucleophilic displaceable leaving group such as halide, alkyl or arylsulfonates or alkyl sulfates) to provide the alkyl substitutedintermediate 9. Isatoic anhydrides of Formula 8 may be made by methodsdescribed in Coppola, Synthesis 1980, 505-36.

[0068] As shown in Scheme 7, an alternate procedure for the preparationof specific compounds of Formula Ic involves reaction of an amine 7 witha benzoxazinone of Formula 10.

[0069] The reaction of Scheme 7 can be run neat or in a variety ofsuitable solvents including tetrahydrofuran, diethyl ether, pyridine,dichloromethane or chloroform with optimum temperatures ranging fromroom temperature to the reflux temperature of the solvent. The generalreaction of benzoxazinones with amines to produce anthranilamides iswell documented in the chemical literature. For a review ofbenzoxazinone chemistry see Jakobsen et al., Biorganic and MedicinalChemistry 2000, 8, 2095-2103 and references cited therein. See alsoCoppola, J. Heterocyclic Chemistry 1999, 36, 563-588.

[0070] Benzoxazinones of Formula 10 can be prepared by a variety ofprocedures. Two procedures that are especially useful are detailed inSchemes 8-9. In Scheme 8, a benzoxazinone of Formula 10 is prepareddirectly via coupling of a pyrazolecarboxylic acid of Formula 4a with ananthranilic acid of Formula 11.

[0071] This involves sequential addition of methanesulfonyl chloride inthe presence of a tertiary amine such as triethylamine or pyridine to apyrazolecarboxylic acid of Formula 4a, followed by the addition of ananthranilic acid of Formula 11, followed by a second addition oftertiary amine and methanesulfonyl chloride. This procedure generallyaffords good yields of the benzoxazinone and is illustrated with greaterdetail in Examples 6 and 8.

[0072] Scheme 9 depicts an alternate preparation for benzoxazinones ofFormula 10 involving coupling of a pyrazole acid chloride of Formula 3awith an isatoic anhydride of Formula 8 to provide the Formula 10benzoxazinone directly.

[0073] Solvents such as pyridine or pyridine/acetonitrile are suitablefor this reaction. The acid chlorides of Formula 3a are available fromthe corresponding acids of Formula 4a by a variety of synthetic methodssuch as chlorination with thionyl chloride or oxalyl chloride.

[0074] Isatoic anhydrides of Formula 8 can be prepared from isatins ofFormula 13 as outlined in Scheme 10.

[0075] Isatins of Formula 13 are obtained from aniline derivatives ofFormula 12 using methods known in the literature. Oxidation of isatin 13with hydrogen peroxide generally affords good yields of thecorresponding isatoic anhydride 8 (Angew. Chem. Int. Ed. Engl. 1980, 19,222-223). Isatoic anhydrides are also available from the anthranilicacids 11 via many known procedures involving reaction of 11 withphosgene or a phosgene equivalent.

[0076] The syntheses of representative acids of Formula 4 are depictedin Schemes 11-16. Syntheses of pyrazoles of Formula 4a are shown inScheme 11.

[0077] The synthesis of compounds of Formula 4a in Scheme 11 involves asthe key step introduction of the R⁷ substituent via alkylation orarylation of the pyrazole of Formula 14 with compounds of Formula 15(wherein Lg is a leaving group as defined above). Oxidation of themethyl group affords the pyrazole carboxylic acid. Some of the morepreferred R⁶ groups include haloalkyl.

[0078] Synthesis of pyrazoles of Formula 4a is also shown in Scheme 12.

[0079] These acids may be prepared via metallation and carboxylation ofcompounds of Formula 18 as the key step. The R⁷ group is introduced in amanner similar to that of Scheme 11, i.e. via alkylation or arylationwith a compound of Formula 15. Representative R⁶ groups include e.g.cyano, haloalkyl and halogen.

[0080] This procedure is particularly useful for preparing1-(2-pyridinyl)pyrazolecarboxylic acids of Formula 4b as shown in Scheme13.

[0081] Reaction of a pyrazole of Formula 17 with a 2,3-dihalopyridine ofFormula 15a affords good yields of the 1-pyridylpyrazole of Formula 18awith good specificity for the desired regiochemistry. Metallation of 18awith lithium diisopropylamide (LDA) followed by quenching of the lithiumsalt with carbon dioxide affords the 1-(2-pyridinyl)pyrazole-carboxylicacid of Formula 4b. Additional details for these procedures are providedin Examples 1, 3, 6, 8 and 10.

[0082] The synthesis of pyrazoles of Formula 4c is described in Scheme14.

[0083] Scheme 14 involves reaction of an optionally substituted phenylhydrazine of Formula 19 with a ketopyruvate of Formula 20 to yieldpyrazole esters of Formula 21. Hydrolysis of the esters affords thepyrazole acids of Formula 4c. This procedure is particularly useful forthe preparation of compounds in which R⁷ is optionally substitutedphenyl and R⁶ is haloalkyl.

[0084] An alternate synthesis of pyrazole acids of Formula 4c isdescribed in Scheme 15.

[0085] The method of Scheme 15 involves 3+2 cycloaddition of anappropriately substituted iminohalide 22 with either substitutedpropiolates of Formula 23 or acrylates of Formula 25. Cycloaddition withan acrylate requires additional oxidation of the intermediate pyrazolineto the pyrazole. Hydrolysis of the esters affords the pyrazole acids ofFormula 4c. Preferred iminohalides for this reaction include thetrifuoromethyl iminochloride of Formula 26 and the iminodibromide ofFormula 27. Compounds such as 26 are known (J. Heterocycl. Chem. 1985,22 (2), 565-8). Compounds such as 27 are available by known methods(Tetrahedron Letters 1999, 40, 2605). These procedures are particularlyuseful for the preparation of compounds where R⁷ is optionallysubstituted phenyl and R⁶ is haloalkyl or bromo.

[0086] The starting pyrazoles of Formula 17 are known compounds or canbe prepared according to known methods. The pyrazole of Formula 17a (thecompound of Formula 17 wherein R⁶ is CF₃ and R⁸ is H) can be prepared byliterature procedures (J. Fluorine Chem. 1991, 53(1), 61-70). Thepyrazoles of Formula 17c (compounds of Formula 17 wherein R⁶ is Cl or Brand R⁸ is H) can also be prepared by literature procedures (Chem. Ber.1966, 99(10), 3350-7). A useful alternative method for the preparationof compound 17c is depicted in Scheme 16.

[0087] In the method of Scheme 16, metallation of the sulfamoyl pyrazoleof Formula 28 with n-butyllithium followed by direct halogenation of theanion with either hexachloroethane (for R⁶ being Cl) or1,2-dibromotetrachloroethane (for R⁶ being Br) affords the halogenatedderivatives of Formula 29. Removal of the sulfamoyl group withtrifluoroacetic acid (TFA) at room temperature proceeds cleanly and ingood yield to afford the pyrazoles of Formula 17c. One skilled in theart will recognize that Formula 17c is a tautomer of Formula 17b.Further experimental details for these procedures are described inExamples 8 and 10.

[0088] Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is H, C₁-C₆alkyl or C₁-C₆ haloalkyl can be prepared by the method outlined inScheme 17.

[0089] Reaction of a compound of Formula 30 wherein R¹³ is C₁-C₄ alkylwith a suitable base in a suitable organic solvent affords the cyclizedproduct of Formula 31 after neutralization with an acid such as aceticacid. The suitable base can be, for example but not limitation, sodiumhydride, potassium t-butoxide, dimsyl sodium (CH₃S(O)CH₂ ⁻Na⁺), alkalimetal (such as lithium, sodium or potassium) carbonates or hydroxides,tetraalkyl (such as methyl, ethyl or butyl)ammonium fluorides orhydroxides, or2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphonine.The suitable organic solvent can be, for example but not limitation,acetone, acetonitrile, tetrahydrofuran, dichloromethane,dimethylsulfoxide, or N,N-dimethylformamide. The cyclization reaction isusually conducted in a temperature range from about 0 to 120° C. Theeffects of solvent, base, temperature and addition time are allinterdependent, and choice of reaction conditions is important tominimize the formation of byproducts. A preferred base istetrabutylammonium fluoride.

[0090] Dehydration of the compound of Formula 31 to give the compound ofFormula 32, followed by converting the carboxylic ester function tocarboxylic acid, affords the compound of Formula 4d. The dehydration iseffected by treatment with a catalytic amount of a suitable acid. Thiscatalytic acid can be, for example but not limitation, sulfuric acid.The reaction is generally conducted using an organic solvent. As oneskilled in the art will realize, dehydration reactions may be conductedin a wide variety of solvents in a temperature range generally betweenabout 0 and 200° C,, more preferably between about 0 and 100° C. For thedehydration in the method of Scheme 17, a solvent comprising acetic acidand temperatures of about 65° C. are preferred. Carboxylic estercompounds can be converted to carboxylic acid compounds by numerousmethods including nucleophilic cleavage under anhydrous conditions orhydrolytic methods involving the use of either acids or bases (see T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nded., John Wiley & Sons, Inc., New York, 1991, pp. 224-269 for a reviewof methods). For the method of Scheme 17, base-catalyzed hydrolyticmethods are preferred. Suitable bases include alkali metal (such aslithium, sodium or potassium) hydroxides. For example, the ester can bedissolved in a mixture of water and an alcohol such as ethanol. Upontreatment with sodium hydroxide or potassium hydroxide, the ester issaponified to provide the sodium or potassium salt of the carboxylicacid. Acidification with a strong acid, such as hydrochloric acid orsulfuric acid, yields the carboxylic acid of Formula 4d. The carboxylicacid can be isolated by methods known to those skilled in the art,including crystallization, extraction and distillation.

[0091] Compounds of Formula 30 can be prepared by the method outlined inScheme 18.

[0092] wherein R⁶ is H, C₁-C₆ alkyl or C₁-C₆ haloalkyl and R¹³ is C₁-C₄alkyl

[0093] Treatment of a hydrazine compound of Formula 33 with a ketone ofFormula 34 in a solvent such as water, methanol or acetic acid gives thehydrazone of Formula 35. One skilled in the art will recognize that thisreaction may require catalysis by an optional acid and may also requireelevated temperatures depending on the molecular substitution pattern ofthe hydrazone of Formula 35. Reaction of the hydrazone of Formula 35with the compound of Formula 36 in a suitable organic solvent such as,for example but not limitation, dichloromethane or tetrahydrofuran inthe presence of an acid scavenger such as triethylamine provides thecompound of Formula 30. The reaction is usually conducted at atemperature between about 0 and 100° C. Further experimental details forthe method of Scheme 18 are illustrated in Example 17. Hydrazinecompounds of Formula 33 can be prepared by standard methods, such as bycontacting the corresponding halo compound of Formula 15a withhydrazine.

[0094] Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is halogen canbe prepared by the method outlined in Scheme 19.

[0095] wherein R¹³ is C₁-C₄ alkyl.

[0096] Oxidization of the compound of Formula 37 optionally in thepresence of acid to give the compound of Formula 32 followed byconversion of the carboxylic ester function to the carboxylic acidprovides the compound of Formula 4d. The oxidizing agent can be hydrogenperoxide, organic peroxides, potassium persulfate, sodium persulfate,ammonium persulfate, potassium monopersulfate (e.g., Oxone®) orpotassium permanganate. To obtain complete conversion, at least oneequivalent of oxidizing agent versus the compound of Formula 37 shouldbe used, preferably between about one to two equivalents. This oxidationis typically carried out in the presence of a solvent. The solvent canbe an ether, such as tetrahydrofuran, p-dioxane and the like, an organicester, such as ethyl acetate, dimethyl carbonate and the like, or apolar aprotic organic such as N,N-dimethylformamide, acetonitrile andthe like. Acids suitable for use in the oxidation step include inorganicacids, such as sulfuric acid, phosphoric acid and the like, and organicacids, such as acetic acid, benzoic acid and the like. The acid, whenused, should be used in greater than 0.1 equivalents versus the compoundof Formula 37. To obtain complete conversion, one to five equivalents ofacid can be used. The preferred oxidant is potassium persulfate and theoxidation is preferably carried out in the presence of sulfuric acid.The reaction can be carried out by mixing the compound of Formula 37 inthe desired solvent and, if used, the acid. The oxidant can then beadded at a convenient rate. The reaction temperature is typically variedfrom as low as about 0° C. up to the boiling point of the solvent inorder to obtain a reasonable reaction time to complete the reaction,preferably less than 8 hours. The desired product, a compound of Formula32 can be isolated by methods known to those skilled in the art,including crystallization, extraction and distillation. Methods suitablefor converting the ester of Formula 32 to the carboxylic acid of Formula4d are already described for Scheme 17. Further experimental details forthe method of Scheme 19 are illustrated in Examples 12 and 13.

[0097] Compounds of Formula 37 can be prepared from correspondingcompounds of Formula 38 as shown in Scheme 20.

[0098] wherein R¹³ is C₁-C₄ alkyl and R⁶ is halogen.

[0099] Treatment of a compound of Formula 38 with a halogenatingreagent, usually in the presence of a solvent, affords the correspondinghalo compound of Formula 37. Halogenating reagents that can be usedinclude phosphorus oxyhalides, phosphorus trihalides, phosphoruspentahalides, thionyl chloride, dihalotrialkylphosphoranes,dihalodiphenylphosphoranes, oxalyl chloride and phosgene. Preferred arephosphorus oxyhalides and phosphorus pentahalides. To obtain completeconversion, at least 0.33 equivalents of phosphorus oxyhalide versus thecompound of Formula 38 (i.e. the mole reatio of phosphorus oxyhalide toFormula 18 is at least 0.33) should be used, preferably between about0.33 and 1.2 equivalents. To obtain complete conversion, at least 0.20equivalents of phosphorus pentahalide versus the compound of Formula 38should be used, preferably between about 0.20 and 1.0 equivalents.Compounds of Formula 38 wherein R¹³ is C₁-C₄ alkyl are preferred forthis reaction. Typical solvents for this halogenation includehalogenated alkanes, such as dichloromethane, chloroform, chlorobutaneand the like, aromatic solvents, such as benzene, xylene, chlorobenzeneand the like, ethers, such as tetrahydrofuran, p-dioxane, diethyl ether,and the like, and polar aprotic solvents such as acetonitrile,N,N-dimethylformamide, and the like. Optionally, an organic base, suchas triethylamine, pyridine, N,N-dimethylaniline or the like, can beadded. Addition of a catalyst, such as N,N-dimethylformamide, is also anoption. Preferred is the process in which the solvent is acetonitrileand a base is absent. Typically, neither a base nor a catalyst isrequired when acetonitrile solvent is used. The preferred process isconducted by mixing the compound of Formula 38 in acetonitrile. Thehalogenating reagent is then added over a convenient time, and themixture is then held at the desired temperature until the reaction iscomplete. The reaction temperature is typically between 20° C. and theboiling point of acetonitrile, and the reaction time is typically lessthan 2 hours. The reaction mass is then neutralized with an inorganicbase, such as sodium bicarbonate, sodium hydroxide and the like, or anorganic base, such as sodium acetate. The desired product, a compound ofFormula 37, can be isolated by methods known to those skilled in theart, including crystallization, extraction and distillation.

[0100] Alternatively, compounds of Formula 37 wherein R⁶ is halogen canbe prepared by treating the corresponding compounds of Formula 37wherein R⁶ is a different halogen (e.g., Cl for making Formula 37wherein R³ is Br) or a sulfonate group such as p-toluenesulfonate,benzenesulfonate and methanesulfonate with the appropriate hydrogenhalide. By this method the R⁶ halogen or sulfonate substituent on theFormula 37 starting compound is replaced with, for example, Br or Clfrom hydrogen bromide or hydrogen chloride, respectively. The reactionis conducted in a suitable solvent such as dibromomethane,dichloromethane or acetonitrile. The reaction can be conducted at ornear atmospheric pressure or above atmospheric pressure in a pressurevessel. When R⁶ in the starting compound of Formula 37 is a halogen suchas Cl, the reaction is preferably conducted in such a way that thehydrogen halide generated from the reaction is removed by sparging orother suitable means. The reaction can be conducted between about 0 and100° C., most conveniently near ambient temperature (e.g., about 10 to40° C.), and more preferably between about 20 and 30° C. Addition of aLewis acid catalyst (such as aluminum tribromide for preparing Formula37 wherein R⁶ is Br) can facilitate the reaction. The product of Formula37 is isolated by the usual methods known to those skilled in the art,including extraction, distillation and crystallization. Further detailsfor this process are illustrated in Example 14.

[0101] Starting compounds of Formula 37 wherein R⁶ is Cl or Br can beprepared from corresponding compounds of Formula 38 as alreadydescribed. Starting compounds of Formula 37 wherein R⁶ is a sulfonategroup can likewise be prepared from corresponding compounds of Formula38 by standard methods such as treatment with a sulfonyl chloride (e.g.,p-toluenesulfonyl chloride) and base such as a tertiary amine (e.g.,triethylamine) in a suitable solvent such as dichloromethane; furtherdetails for this process are illustrated in Example 15.

[0102] Pyrazolecarboxylic acids of Formula 4d wherein R⁶ is C₁-C₄ alkoxyor C₁-C₄ haloalkoxy can also be prepared by the method outlined inScheme 21.

[0103] wherein R¹³ is C₁-C₄ alkyl, and X is a leaving group.

[0104] In this method, instead of being halogenated as shown in Scheme20, the compound of Formula 38 is oxidized to the compound of Formula32a. The reaction conditions for this oxidation are as already describedfor the conversion of the compound of Formula 37 to the compound ofFormula 32 in Scheme 19.

[0105] The compound of Formula 32a is then alkylated to form thecompound of Formula 32b by contact with an alkylating agent CF₃CH₂X (39)in the presence of a base. In the alkylating agent 39, X is anucleophilic reaction leaving group such as halogen (e.g., Br, I),OS(O)₂CH₃ (methanesulfonate), OS(O)₂CF₃, OS(O)₂Ph-p-CH₃p-toluenesulfonate), and the like; methanesulfonate works well. Thereaction is conducted in the presence of at least one equivalent of abase. Suitable bases include inorganic bases, such as alkali metal (suchas lithium, sodium or potassium) carbonates and hydroxides, and organicbases, such as triethylamine, diisopropylethylamine and1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is generally conductedin a solvent, which can comprise alcohols, such as methanol and ethanol,halogenated alkanes, such as dichloromethane, aromatic solvents, such asbenzene, toluene and chlorobenzene, ethers, such as tetrahydrofuran, andpolar aprotic solvents, such as acetonitrile, such as such asacetonitrile, N,N-dimethylformamide, and the like. Alcohols and polaraprotic solvents are preferred for use with inorganic bases. Potassiumcarbonate as base and acetonitrile as solvent are preferred. Thereaction is generally conducted between about 0 and 150° C., with mosttypically between ambient temperature and 100° C. The product of Formula32b can be isolated by conventional techniques such as extraction. Theester of Formula 32b can then be converted to the carboxylic acid ofFormula 4d by the methods already described for the conversion ofFormula 32 to Formula 4d in Scheme 17. Further experimental details forthe method of Scheme 21 are illustrated in Example 16.

[0106] Compounds of Formula 38 can be prepared from compounds of Formula33 as outlined in Scheme 22.

[0107] wherein R¹³ is C₁-C₄ alkyl.

[0108] In this method, a hydrazine compound of Formula 33 is contactedwith a compound of Formula 40 (a fumarate ester or maleate ester or amixture thereof may be used) in the presence of a base and a solvent.The base is typically a metal alkoxide salt, such as sodium methoxide,potassium methoxide, sodium ethoxide, potassium ethoxide, potassiumtert-butoxide, lithium tert-butoxide, and the like. Greater than 0.5equivalents of base versus the compound of Formula 33 should be used,preferably between 0.9 and 1.3 equivalents. Greater than 1.0 equivalentsof the compound of Formula 40 should be used, preferably between 1.0 to1.3 equivalents. Polar protic and polar aprotic organic solvents can beused, such as alcohols, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide and the like. Preferredsolvents are alcohols such as methanol and ethanol. It is especiallypreferred that the alcohol be the same as that making up the fumarate ormaleate ester and the alkoxide base. The reaction is typically conductedby mixing the compound of Formula 33 and the base in the solvent. Themixture can be heated or cooled to a desired temperature and thecompound of Formula 40 added over a period of time. Typically reactiontemperatures are between 0° C. and the boiling point of the solventused. The reaction may be conducted under greater than atmosphericpressure in order to increase the boiling point of the solvent.Temperatures between about 30 and 90° C. are generally preferred. Theaddition time can be as quick as heat transfer allows. Typical additiontimes are between 1 minute and 2 hours. Optimum reaction temperature andaddition time vary depending upon the identities of the compounds ofFormula 33 and Formula 40. After addition, the reaction mixture can beheld for a time at the reaction temperature. Depending upon the reactiontemperature, the required hold time may be from 0 to 2 hours. Typicalhold times are 10 to 60 minutes. The reaction mass then can be acidifiedby adding an organic acid, such as acetic acid and the like, or aninorganic acid, such as hydrochloric acid, sulfuric acid and the like.Depending on the reaction conditions and the means of isolation, the—CO₂R¹³ function on the compound of Formula 38 may be hydrolyzed to—CO₂H; for example, the presence of water in the reaction mixture canpromote such hydrolysis. If the carboxylic acid (—CO₂H) is formed, itcan be converted back to —CO₂R¹³ wherein R¹³ is C₁-C₄ alkyl usingesterification methods well-known in the art. The desired product, acompound of Formula 38, can be isolated by methods known to thoseskilled in the art, such as crystallization, extraction or distillation.

[0109] It is recognized that some reagents and reaction conditionsdescribed above for preparing compounds of Formula I may not becompatible with certain functionalities present in the intermediates. Inthese instances, the incorporation of protection/deprotection sequencesor functional group interconversions into the synthesis will aid inobtaining the desired products. The use and choice of the protectinggroups will be apparent to one skilled in chemical synthesis (see, forexample, Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art willrecognize that, in some cases, after the introduction of a given reagentas it is depicted in any individual scheme, it may be necessary toperform additional routine synthetic steps not described in detail tocomplete the synthesis of compounds of Formula I. One skilled in the artwill also recognize that it may be necessary to perform a combination ofthe steps illustrated in the above schemes in an order other than thatimplied by the particular sequence presented to prepare the compounds ofFormula I.

[0110] It is believed that one skilled in the art using the precedingdescription can prepare compounds of Formula I of the present inventionto its fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative, and not limiting of the disclosure inany way whatsoever. Percentages are by weight except for chromatographicsolvent mixtures or where otherwise indicated. Parts and percentages forchromatographic solvent mixtures are by volume unless otherwiseindicated. ¹H NMR spectra are reported in ppm downfield fromtetramethylsilane; s means singlet, d means doublet, t means triplet, qmeans quartet, m means multiplet, dd means doublet of doublets, dt meansdoublet of triplets, br s means broad singlet.

EXAMPLE 1 Preparation of 2-[1-Ethyl-3-trifluoromethylpyrazol-5-ylcarbamoyl]-3-methyl-N-(1-methylethyl)benzamide Step A: Preparation of3-Methyl-N-(1-methylethyl)-2-nitrobenzamide

[0111] A solution of 3-methyl-2-nitrobenzoic acid (2.00 g, 11.0 mmol)and triethylamine (1.22 g, 12.1 mmol) in 25 mL of methylene chloride wascooled to 10° C. Ethyl chloroformate was carefully added and a solidprecipitate formed. After stirring for 30 minutes isopropylamine (0.94g, 16.0 mmol) was added and a homogeneous solution resulted. Thereaction was stirred for an additional hour, poured into water andextracted with ethyl acetate. The organic extracts were washed withwater, dried over magnesium sulfate and evaporated under reducedpressure to afford 1.96 g of the desired intermediate as a white solidmelting at 126-128° C.

[0112]¹H NMR (CDCl₃) δ 1.24 (d, 6H), 2.38 (s, 3H), 4.22 (m, 1H), 5.80(br s, 1H), 7.4 (m, 3H).

Step B: Preparation of 2-Amino-3-methyl-N-(1-methylethyl)benzamide

[0113] The 2-nitrobenzamide of Step A (1.70 g, 7.6 mmol) washydrogenated over 5% Pd/C in 40 mL of ethanol at 50 psi. When the uptakeof hydrogen ceased the reaction was filtered through Celite®diatomaceous filter aid and the Celite® was washed with ether. Thefiltrate was evaporated under reduced pressure to afford 1.41 g of thetitle compound as a solid melting at 149-151° C.

[0114]¹H NMR (CDCl₃) δ 1.24 (dd, 6H), 2.16 (s, 3H), 4.25 (m, 1H), 5.54(br s, 2H), 5.85 (br s, 1H), 6.59 (t, 1H), 7.13 (d, 1H), 7.17 (d, 1H).

Step C: Preparation of 1-Ethyl-3-trifluoromethylpyrazol-5-yl carboxylicacid

[0115] To a mixture of 3-trifluoromethylpyrazole (5 g, 37 mmol) andpowdered potassium carbonate (10 g, 72 mmol) stirring in 30 mL ofN,N-dimethylformamide, iodoethane (8 g, 51 mmol) was added dropwise.After a mild exotherm, the reaction was stirred overnight at roomtemperature. The reaction mixture was partitioned between 100 mL ofdiethyl ether and 100 mL of water. The ether layer was separated, washedwith water (3×) and brine, and dried over magnesium sulfate. Evaporationof solvent in vacuo gave 4 g of oil.

[0116] To 3.8 g of this oil stirring in 40 mL of tetrahydrofuran undernitrogen in a dry ice/acetone bath, 17 mL of a 2.5 M solution ofn-butyllithium in tetrahydrofuran (43 mmol) was added dropwise and thesolution stirred for 20 minutes at −78° C. An excess of gaseous carbondioxide was bubbled into the stirred solution at a moderate rate for 10minutes. After addition of carbon dioxide, the reaction was allowed toslowly reach room temperature and stirred overnight. The reactionmixture was partitioned between diethyl ether (100 mL) and 0.5 N aqueoussodium hydroxide (100 mL). The basic layer was separated and acidifiedwith concentrated hydrochloric acid to a pH of 2-3. The aqueous mixturewas extracted with ethyl acetate (100 mL) and the organic extract washedwith water and brine and dried over magnesium sulfate. The oily residue,which remained after evaporating the solvent in vacuo, was triturated toa solid from a small amount of 1-chlorobutane. After filtering anddrying, a slightly impure sample of1-ethyl-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (1.4 g) wasobtained as a broad-melting solid.

[0117]¹H NMR(CDCl₃) δ 1.51 (t, 3H), 4.68 (q, 2H), 7.23 (s, 1H), 9.85 (brs, 1H).

Step D: Preparation of 2-[1-Ethyl-3-trifluoromethylpyrazol-5-ylcarbamoyl]-3-methyl-N-(1-methylethyl)benzamide

[0118] To a solution of 1-ethyl-3-trifluoromethyl-pyrazol-5-ylcarboxylic acid (i.e. the product of Step C) (0.5 g, 2.4 mmol) stirringin 20 mL of methylene chloride, oxalyl chloride (1.2 mL, 14 mmol) wasadded. Upon addition of 2 drops of N,N-dimethylformamide, foaming andbubbling occurred. The reaction mixture was heated at reflux for 1 hr asa yellow solution. After cooling, the solvent was removed in vacuo andthe resulting residue dissolved in 20 mL of tetrahydrofuran. To thestirred solution, 2-amino-3-methyl-N-(1-methylethyl)benzamide (i.e. theproduct of Step B) (0.7 g, 3.6 mmol) was added followed by the dropwiseaddition of N,N-diisopropylethylamine (3 mL, 17 mmol). After stirring atroom temperature overnight, the reaction mixture was partitioned betweenethyl acetate (100 mL) and 1N aqueous hydrochloric acid (75 mL). Theseparated organic layer was washed with water and brine and dried overmagnesium sulfate. Evaporating in vacuo gave a white solid residue,which on purification by flash column chromatography on silica gel (2:1hexanes/ethyl acetate) afforded 0.5 g of the tide compound, a compoundof the present invention, melting at 223-226° C.

[0119]¹H NMR (DMSO-d₆) δ 1.06 (d, 6H), 1.36 (t, 3H), 2.45 (s, 3H), 3.97(m, 1H), 4.58 (q, 2H), 7.43-7.25 (m, 3H), 7.45 (s, 1H), 8.05 (d, 1H),10.15 (s, 1H).

EXAMPLE 2 Preparation ofN-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl)phenyl]-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideStep A: Preparation of 2-Methyl-1-phenyl-4-(trifluoromethyl)-1H-pyrazole

[0120] A solution of 1,1,1-trifluoropentane-2,4-dione (20.0 g, 0.130mole) in glacial acetic acid (60 mL) was cooled to 7° C. using anice/water bath. Phenylhydrazine (14.1 g, 0.130 mole) was added dropwiseover a period of 60 minutes. The reaction mass temperature increased to15° C. during the addition. The resulting orange solution was held underambient conditions for 60 minutes. The bulk of the acetic acid wasremoved by stripping on a rotary evaporator at a bath temperature of 65°C. The residue was dissolved in methylene chloride (150 mL). Thesolution was washed with aqueous sodium bicarbonate (3 g in 50 mL ofwater). The purple-red organic layer was separated, treated withactivated charcoal (2 g) and MgSO₄, then filtered. Volatiles wereremoved on a rotary evaporator. The crude product consisted of 28.0 g ofa rose-colored oil, which contained ˜89% the desired product and 11%1-phenyl-5-(trifluoromethyl)-3-methylpyrazole.

[0121]¹H NMR (DMSO-d₆) δ 2.35 (s, 3H), 6.76 (s, 1H), 7.6-7.5 (m, 5H).

Step B: Preparation of1-Phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0122] A sample of crude2-methyl-1-phenyl-4-(trifluoromethyl)-1H-pyrazole (i.e. the product ofStep A) (89%, 50.0 g, 0.221 mole) was mixed with water (400 mL) andcetyltrimethylammonium chloride (4.00 g, 0.011 mole). The mixture washeated to 95° C. Potassium permanganate was added in 10 equal portions,spaced at ˜8 minute intervals. The reaction mass was maintained at95-100° C. during this period. After the last portion was added, themixture was held for ˜15 minutes at 95-100° C., whereupon the purple,permanganate color had been discharged. The reaction mass was filteredwhile hot (˜75° C.) through a 1-cm bed of Celite® diatomaceous filteraid in a 150-mL coarse glass frit funnel. The filter cake was washedwith warm (˜50° C.) water (3×100 mL). The combined filtrate and washingswere extracted with ether (2×100 mL) to remove a small amount of yellow,water-insoluble material. The aqueous layer was purged with nitrogen toremove residual ether. The clear, colorless alkaline solution wasacidified by adding concentrated hydrochloric acid dropwise until the pHreached ˜1.3 (28 g, 0.28 mole). Gas evolution was vigorous during thefirst two-thirds of the addition. The product was collected viafiltration, washed with water (3×40 mL), then dried overnight at 55° C.in vacuo. The product consisted of 11.7 g of a white, crystallinepowder, which was essentially pure based upon ¹ H NMR.

[0123]¹H NMR (CDCl₃) δ 7.33 (s, 1H), 7.4-7.5 (m, 5H).

Step C: Preparation of1-Phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride

[0124] A sample of crude1-phenyl-3-(trifluoromethyl)pyrazole-5-carboxylic acid (i.e. the productof Step B) (4.13 g, 16.1 mmol) was dissolved in methylene chloride (45mL). The solution was treated with oxalyl chloride (1.80 mL, 20.6 mmol),followed by N,N-dimethylformamide (0.010 mL, 0.13 mmol). Off-gassingbegan shortly after adding the N,N-dimethylformamide catalyst. Thereaction mixture was stirred for ˜20 minutes under ambient conditions,then was heated to reflux for a period of 35 minutes. Volatiles wereremoved by stripping the reaction mixture on a rotary evaporator at abath temperature of 55° C. The product consisted of 4.43 g of alight-yellow oil. The only impurity observed by ¹H NMR wasN,N-dimethylformamide.

[0125]¹H NMR (CDCl₃) δ 7.40 (m, 1H), 7.42 (s, 1H), 7.50-7.53 (m, 4H).

Step D: Preparation ofN-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0126] A sample of 3-methylisatoic anhydride (0.30 g, 1.7 mmol)partially dissolved in pyridine (4.0 mL) was treated with1-phenyl-3-(trifluoromethylpyrazole)-5-carboxyl chloride (i.e. theproduct of Step C) (0.55 g, 1.9 mmol). The mixture was heated to ˜95° C.for a period of 2 hours. The resulting orange solution was cooled to 29°C., then was treated with isopropylamine (1.00 g, 16.9 mmol). Thereaction mass exothermically warmed to 39° C. It was further heated to55° C. for a period of 30 minutes, whereupon much precipitate formed.The reaction mass was dissolved in dichloromethane (150 mL). Thesolution was washed with aqueous acid (5 mL of conc. HCl in 45 mL ofwater), then with aqueous base (2 g sodium carbonate in 50 mL of water).The organic layer was dried over MgSO₄, filtered, then concentrated on arotary evaporator. Upon reduction to ˜4 mL, product crystals had formed.The slurry was diluted with ˜10 mL of ether, whereupon more productprecipitated. The product was isolated by filtration, washed with ether(2×10 mL), then washed with water (2×50 mL). The wet cake was dried for30 minutes at 70° C. in vacuo. The product, a compound of the presentinvention, consisted of 0.52 g of an off-white powder melting at260-262° C.

[0127]¹H NMR (DMSO-d₆) δ 1.07 (d, 6H), 2.21 (s, 3H), 4.02 (octet, 1H),7.2-7.4 (m, 3H), 7.45-7.6 (m, 6H), 8.10 (d, 1H), 10.31 (s, 1H).

EXAMPLE 3 Preparation ofN-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxamideStep A: Preparation of3-Trifluoromethyl-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

[0128] A mixture of 2-chloro-3-trifluoromethylpyridine (3.62 g., 21mmol), 3-trifluoro-methylpyrazole (2.7 g., 20 mmol), and potassiumcarbonate (6.0 g, 43 mmol) were heated at 100° C. for 18 h. The cooledreaction mixture was added to ice/water (100 mL). The mixture wasextracted twice with ether (100 mL) and the combined ether extracts werewashed twice with water (100 mL). The organic layer was dried withmagnesium sulfate and concentrated to an oil. Chromatography on silicagel with hexanes:ethyl acetate 8:1 to 4:1 as eluent gave the titlecompound (3.5 g) as an oil.

[0129]¹H NMR (CDCl₃) δ 6.75 (m, 1H), 7.5 (m, 1H), 8.2 (m, 2H), 8.7 (m,1H).

Step B: Preparation of3-(Trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxylicacid

[0130] A mixture of the title compound of Example 3, Step A (3.4 g, 13mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to −70° C.Lithium diisopropylamide (2N in heptane/tetrahydrofuran, (Aldrich) 9.5mL, 19 mmol) was added and the resulting dark mixture was stirred for 10minutes. Dry carbon dioxide was bubbled through the mixture for 15minutes. The mixture was allowed to warm to 23° C. and treated withwater (50 mL) and 1N sodium hydroxide (10 mL). The aqueous mixture wasextracted with ether (100 mL) and then ethyl acetate (100 mL). Theaqueous layer was acidified with 6N hydrochloric acid to pH 1-2 andextracted twice with dichloromethane. The organic layer was dried withmagnesium sulfate and concentrated to give the title compound (1.5 g).

[0131]¹H NMR (CDCl₃) δ 7.6 (m, 1H), 7.95 (m, 1H), 8.56 (m, 1H), 8.9 (m,1H), 14.2 (br, 1H)

Step C: Preparation ofN-[2-Methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-3-(trifluoromethyl)-1-[3-(trifluoromethyl)-2-pyridinyl]-1H-pyrazole-5-carboxamide

[0132] A mixture of the title compound of Example 3, Step B (0.54 g, 1.1mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) andBOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1mmol) in acetonitrile (13 mL) was treated with triethylamine (0.9 mL).The mixture was shaken in a closed scintillation vial for 18 h. Thereaction was partitioned between ethyl acetate (100 mL) and 1Nhydrochloric acid. The ethyl acetate layer was washed successively with1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturatedsodium chloride solution (50 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was subjected to columnchromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) aseluent. The title compound (0.43 g), a compound of the presentinvention, was isolated as a white solid. m.p. 227-230° C.

[0133]¹H NMR (CDCl₃) δ 1.2 (m, 6H), 4.15 (m, 1H), 5.9 (br d, 1H), 7.1(m, 1H), 7.2 (m, 2H), 7.4 (s, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.74 (m,1H), 10.4 (br, 1H).

EXAMPLE 4 Preparation of1-(3-Chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideStep A: Preparation of3-Chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

[0134] To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and3-(trifluoromethyl)-pyrazole (83 g, 0.61 mol) in dryN,N-dimethylformamide (300 mL) was added potassium carbonate (166.0 g,1.2 mol) and the reaction was then heated to 110-125° C. over 48 hours.The reaction was cooled to 100° C. and filtered through Celite®diatomaceous filter aid to remove solids. N,N-Dimethylformamide andexcess dichloropyridine were removed by distillation at atmosphericpressure. Distillation of the product at reduced pressure (b.p. 139-141°C., 7 mm) afforded the desired intermediate as a clear yellow oil (113.4g).

[0135]¹H NMR (CDCl₃) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15(s, 1H), 8.45 (d, 1H).

Step B: Preparation of1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0136] To a solution of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (i.e. theproduct of Step A) (105.0 g, 425 mmol) in dry tetrahydrofuran (700 mL)at −75° C. was added via cannula a −30° C. solution of lithiumdiisopropylamide (425 mmol) in dry tetrahydrofuran (300 mL). The deepred solution was stirred for 15 minutes, after which time carbon dioxidewas bubbled through at −63° C. until the solution became pale yellow andthe exothermicity ceased. The reaction was stirred for an additional 20minutes and then quenched with water (20 mL). The solvent was removedunder reduced pressure, and the reaction mixture partitioned betweenether and 0.5N aqueous sodium hydroxide solution. The aqueous extractswere washed with ether (3×), filtered through Celite® diatomaceousfilter aid to remove residual solids, and then acidified to a pH ofapproximately 4, at which point an orange oil formed. The aqueousmixture was stirred vigorously and additional acid was added to lowerthe pH to 2.5-3. The orange oil congealed into a granular solid, whichwas filtered, washed successively with water and IN hydrochloric acid,and dried under vacuum at 50° C. to afford the title product as anoff-white solid (130 g). (Product from another run following similarprocedures melted at 175-176° C.)

[0137]¹H NMR (DMSO-d₆) δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60(d, 1H).

Step C: Preparation of 8-Methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[0138] To a solution of 2-amino-3-methylbenzoic acid (6 g) in dry1,4-dioxane (50 mL) was added dropwise a solution of trichloromethylchloroformate (8 mL) in dry 1,4-dioxane (25 mL), with ice-water coolingto keep the reaction temperature below 25° C. A white precipitate beganto form during the addition. The reaction mixture was stirred at roomtemperature overnight. The precipitated solids were removed byfiltration and washed with 1,4-dioxane (2×20 mL) and hexane (2×15 mL)and air-dried to yield 6.51 g of off-white solid.

[0139]¹H NMR (DMSO-d₆) δ 2.33 (s, 3H), 7.18 (t, 1H), 7.59 (d, 1H), 7.78(d, 1H), 11.0 (br s, 1H).

Step D: Preparation of2-[1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0140] To a suspension of the carboxylic acid product prepared as inStep B (146 g, 500 mmol) in dichloromethane (approximately 2 L) wasadded N,N-dimethylformamide (20 drops) and oxalyl chloride (67 mL, 750mmol) in approximately 5-mL portions over approximately 2 h. Vigorousgas evolution occurred during the addition. The reaction mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo to provide the crude acid chloride as an opaqueorange mixture. This material was taken up in dichloromethane, filteredto remove some solids and then reconcentrated and used without furtherpurification. The crude acid chloride was dissolved in acetonitrile (250mL) and added to a suspension of the product from Step C in acetonitrile(400 mL). Pyridine (250 mL) was added, the mixture was stirred for 15min at room temperature, then warmed to reflux for 3 h. The resultingmixture was cooled to room temperature and stirred overnight to providea solid mass. Additional acetonitrile was added and the mixture wasmixed to form a thick slurry. The solids were collected and washed withcold acetonitrile. The solids were air-dried and the dried in vacuo at90° C. for 5 h to yield 144.8 g of fluffy white solid.

[0141]¹H NMR (CDCl₃) δ 1.84 (s, 3H), 7.4 (t, 1H), 7.6 (m, 3H), 8.0 (dd,1H), 8.1 (s, 1H), 8.6 (d, 1H).

Step E: Preparation of1-(3-Chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)-amino]carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0142] To a suspension of the benzoxazinone product of Step D (124 g,300 mmol) in dichloromethane (500 mL) was added dropwise isopropylamine(76 mL, 900 mmol) at room temperature. The temperature of the reactionmixture rose and the suspension thinned during the addition. Thereaction mixture was then warmed to reflux for 1.5 h. A new suspensionformed. The reaction mixture was cooled to room temperature and diethylether (1.3 L) was added and the mixture stirred at room temperatureovernight. The solids were collected and washed with ether. The solidswere air-dried and then dried in vacuo at 90° C. for 5 h to yield 122 gof the title compound, a compound of the present invention, as a fluffywhite solid, melting at 194-196° C.

[0143]¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d,1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H),8.5 (d, 1H), 10.4 (s, 1H).

EXAMPLE 5 Alternate preparation of1-(3-chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0144] To a solution of the carboxylic acid product prepared as inExample 4, Step B (28 g, 96 mmol) in dichloromethane (240 mL) was addedN,N-dimethylformamide (12 drops) and oxalyl chloride (15.8 g, 124 mmol).The reaction mixture was stirred at room temperature until gas evolutionceased (approximately 1.5 h). The reaction mixture was concentrated invacuo to provide the crude acid chloride as an oil that was used withoutfurther purification. The crude acid chloride was dissolved inacetonitrile (95 mL) and added to a solution of the benzoxazin-2,4-dioneprepared as in Example 4, Step C in acetonitrile (95 mL). The resultingmixture was stirred at room temperature (approximately 30 min). Pyridine(95 mL) was added and the mixture heated to about 90° C. (approximately1 h). The reaction mixture was cooled to about 35° C. and isopropylamine(25 mL) was added. The reaction mixture exothermically warmed during theaddition and then was maintained at about 50° C. (approximately 1 h).The reaction mixture was then poured into ice water and stirred. Theresulting precipitate was collected by filtration, washed with water anddried in vacuo overnight to provide 37.5 g of the title compound, acompound of the present invention, as a tan solid.

[0145]¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.21 (s, 3H), 4.2 (m, 1H), 5.9 (d,1H), 7.2 (t, 1H), 7.3 (m, 2H), 7.31 (s, 1H), 7.4 (m, 1H), 7.8 (d, 1H),8.5 (d, 1H), 10.4 (s, 1H).

EXAMPLE 6 Preparation ofN-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideStep A: Preparation of 2-Amino-3-methyl-5-chlorobenzoic acid

[0146] To a solution of 2-amino-3-methylbenzoic acid (Aldrich, 15.0 g,99.2 mmol) in N,N-dimethylformamide (50 mL) was addedN-chlorosuccinimide (13.3 g, 99.2 mmol) and the reaction mixture washeated to 100° C. for 30 minutes. The heat was removed, the reaction wascooled to room temperature and let stand overnight. The reaction mixturewas then slowly poured into ice-water (250 mL) to precipitate a whitesolid. The solid was filtered and washed four times with water and thentaken up in ethyl acetate (900 mL). The ethyl acetate solution was driedover magnesium sulfate, evaporated under reduced pressure and theresidual solid was washed with ether to afford the desired intermediateas a white solid (13.9 g).

[0147]¹H NMR (DMSO-d₆) δ 2.11 (s, 3H), 7.22 (s, 1H), 7.55 (s, 1H).

Step B: Preparation of3-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine

[0148] To a mixture of 2,3-dichloropyridine (99.0 g, 0.67 mol) and3-trifluoromethyl pyrazole (83 g, 0.61 mol) in dry N,N-dimethylformamide(300 mL) was added potassium carbonate (166.0 g, 1.2 mol) and thereaction was then heated to 110-125° C. over 48 hours. The reaction wascooled to 100° C. and filtered through Celite® diatomaceous filter aidto remove solids. N,N-Dimethylformamide and excess dichloropyridine wereremoved by distillation at atomospheric pressure. Distillation of theproduct at reduced pressure (b.p. 139-141° C., 7 mm) afforded the titlecompound as a clear yellow oil (113.4 g).

[0149]¹NMR (CDCl₃) δ 6.78 (s, 1H), 7.36 (t, 1H), 7.93 (d, 1H), 8.15 (s,1 H), 8.45 (d, 1H).

Step C: Preparation of1-(3-Chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0150] To a solution of the pyrazole product from Step B (105.0 g, 425mmol) in dry tetrahydrofuran (700 mL) at −75° C. was added via cannula a-30° C. solution of lithium diisopropylamide (425 mmol) in drytetrahydrofuran (300 mL). The deep red solution was stirred for 15minutes, after which time carbon dioxide was bubbled through at −63° C.until the solution became pale yellow and the exothermicity ceased. Thereaction was stirred for an additional 20 minutes and then quenched withwater (20 mL). The solvent was removed under reduced pressure, and thereaction mixture was partitioned between ether and 0.5 N aqueous sodiumhydroxide solution. The aqueous extracts were washed with ether (3×),filtered through Celite® diatomaceous filter aid to remove residualsolids, and then acidified to a pH of approximately 4, at which point anorange oil formed. The aqueous mixture was stirred vigorously andadditional acid was added to lower the pH to 2.5-3. The orange oilcongealed into a granular solid, which was filtered, washed successivelywith water and 1N hydrochloric acid, and dried under vacuum at 50° C. toafford the title product as an off-white solid (130 g). (Product fromanother run following similar procedure melted at 175-176° C.)

[0151]¹H NMR (DMSO-d₆) δ 7.61 (s, 1H), 7.76 (dd, 1H), 8.31 (d, 1H), 8.60(d, 1H).

Step D: Preparation of6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl4H-3,1-benzoxazin4-one

[0152] To a solution of methanesulfonyl chloride (2.2 mL, 28.3 mmol) inacetonitrile (75 mL) was added dropwise a mixture of the carboxylic acidproduct from Step C (7.5 g, 27.0 mmol) and triethylamine (3.75 mL, 27.0mmol) in acetonitrile (75 mL) at 0-5° C. The reaction temperature wasthen maintained at 0° C. throughout successive addition of reagents.After stirring for 20 minutes, 2-amino-3-methyl-5-chlorobenzoic acidfrom Step A (5.1 g, 27.0 mmol) was added and stirring was continued foran additional 5 minutes. A solution of triethylamine (7.5 mL, 54.0 mmol)in acetonitrile (15 mL) was then added dropwise, and the reactionmixture was stirred 45 minutes, followed by the addition ofmethanesulfonyl chloride (2.2 mL, 28.3 mmol). The reaction mixture wasthen warmed to room temperature and stirred overnight. Approximately 75mL of water was then added to precipitate 5.8 g of a yellow solid. Anadditional 1 g of product was isolated by extraction from the filtrateto provide a total of 6.8 g of the title compound as a yellow solid.

[0153]¹H NMR (CDCl₃) δ 1.83 (s, 3H), 7.50 (s, 1H), 7.53 (m, 2H), 7.99(m, 2H), 8.58 (d, 1H).

Step E: Preparation ofN-[4-Chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0154] To a solution of the benzoxazinone product of Step D (5.0 g, 11.3mmol) in tetrahydrofuran (35 mL) was added dropwise isopropylamine(2.9mL, 34.0mmol) in tetrahydrofuran (10 mL) at room temperature. Thereaction mixture was then warmed until all solids had dissolved andstirred an additional five minutes, at which point thin layerchromatography on silica gel confirmed completion of the reaction. Thetetrahydrofuran solvent was evaporated under reduced pressure, and theresidual solid was purified by chromatography on silica gel, followed bytrituration with ether/hexane to afford the title compound, a compoundof the present invention, as a solid (4.6 g), melting at 195-196° C.

[0155]¹H NMR (CDCl₃) δ]1.21 (d, 6H), 2.17 (s, 3H), 4.16 (m, 1H), 5.95(br, d 1H), 7.1-7.3 (m, 2H), 7.39 (s, 1H), 7.4 (m, 1H), 7.84 (d, 1H),8.50 (d, 1H), 10.24 (br s, 1H).

EXAMPLE 7 Preparation ofN-[4-Chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0156] To a solution of the benzoxazinone product of Example 6, Step D(4.50 g, 10.18 mmol) in tetrahydrofuran (THF; 70 mL) was addedmethylamine (2.0 M solution in THF, 15 mL, 30.0 mmol) dropwise and thereaction mixture was stirred at room temperature for 5 minutes. Thetetrahydrofuran solvent was evaporated under reduced pressure and theresidual solid was purified by chromatography on silica gel to afford4.09 g of the title compound, a compound of the present invention, as awhite solid melting at 185-186° C.

[0157]¹H NMR DMSO-d₆) δ 2.17 (s, 3H), 2.65 (d, 3H), 7.35 (d, 1H), 7.46(dd, 1H), 7.65 (dd, 1H), 7.74 (s, 1H), 8.21 (d, 1H), 8.35 (br q, 1H),8.74 (d, 1H), 10.39 (s, 1H).

EXAMPLE 8 Preparation of3-Chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideStep A: Preparation of 3-Chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide

[0158] To a solution of N-dimethylsulfamoylpyrazole (188.0 g, 1.07 mol)in dry tetrahydrofuran (1500 mL) at −78° C. was added dropwise asolution of 2.5 M n-butyllithium (472 mL, 1.18 mol) in hexane whilemaintaining the temperature below −65° C. Upon completion of theaddition the reaction mixture was maintained at −78° C. for anadditional 45 minutes, after which time a solution of hexachloroethane(279 g, 1.18 mol) in tetrahydrofuran (120 mL) was added dropwise. Thereaction mixture was maintained for an hour at −78° C., warmed to −20°C. and then quenched with water (1 L). The reaction mixture wasextracted with methylene chloride (4×500 mL); the organic extracts weredried over magnesium sulfate and concentrated. The crude product wasfurther purified by chromatography on silica gel using methylenechloride as eluent to afford the title product compound as a yellow oil(160 g).

[0159]¹H NMR(CDCl₃) δ 3.07 (d, 6H), 6.33 (s, 1H), 7.61 (s, 1M).

Step B: Preparation of 3-Chloropyrazole

[0160] To trifluoroacetic acid (290 mL) was added dropwise thechloropyrazole product (160 g) from Step A, and the reaction mixture wasstirred at room temperature for 1.5 hours and then concentrated atreduced pressure. The residue was taken up in hexane, insoluble solidswere filtered off, and the hexane was concentrated to afford the crudeproduct as an oil. The crude product was further purified bychromatography on silica gel using ether/hexane (40:60) as eluent toafford the title product as a yellow oil (64.44 g).

[0161]¹H NMR (CDCl₃) δ 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H).

Step C: Preparation of 3-Chloro-2-(3-chloro-1H-pyrazol-1-yl)pyridine

[0162] To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) inN,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g,1.06 mol), and the reaction mixture was then heated to 100° C. for 36hours. The reaction mixture was cooled to room temperature and slowlypoured into ice water. The precipitated solids were filtered and washedwith water. The solid filter cake was taken up in ethyl acetate, driedover magnesium sulfate and concentrated. The crude solid waschromatographed on silica gel using 20% ethyl acetate/hexane as eluentto afford the title product as a white solid (39.75 g).

[0163]¹H NMR (CDCl₃) δ 6.43 (s, 1H), 7.26 (m, 1H), 7.90 (d, 1H), 8.09(s, 1H), 8.41 (d, 1H).

Step D: Preparation of3-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0164] To a solution of the pyrazole product from Step C (39.75 g, 186mmol) in dry tetrahydrofuran (400 mL) at −78° C. was added dropwise asolution of 2.0 M lithium diisopropylamide (93 mL, 186 mmol) intetrahydrofuran. Carbon dioxide was bubbled through the amber solutionfor 14 minutes, after which time the solution became palebrownish-yellow. The reaction was made basic with IN aqueous sodiumhydroxide solution and -extracted with ether (2×500 mL). The aqueousextracts were acidified with 6 N hydrochloric acid and extracted withethyl acetate (3×500 mL). The ethyl acetate extracts were dried overmagnesium sulfate and concentrated to afford the title product as anoff-white solid (42.96 g). (Product from another run following similarprocedure melted at 198-199° C.)

[0165]¹H NMR (DMSO-d₆) δ 6.99 (s, 1H), 7.45 (m, 1H), 7.93 (d, 1H), 8.51(d, 1H).

Step E: Preparation of6-Chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0166] To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) inacetonitrile (150 mL) was added dropwise a mixture of the carboxylicacid product from Step D (15.0 g, 58.16 mmol) and triethylamine (5.88 g,58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture wasthen stirred for 30 minutes at 0° C. Then,2-amino-3-methyl-5-chlorobenzoic acid from Example 6, Step A (10.79 g,58.16 mmol) was added, and stirring was continued for an additional 10minutes. A solution of triethylamine (11.77 g, 116.5 mmol) inacetonitrile was then added dropwise while keeping the temperature below10° C. The reaction mixture was stirred 60 minutes at 0° C., and thenmethanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reactionmixture was then warmed to room temperature and stirred for anadditional 2 hours. The reaction mixture was then concentrated, and thecrude product was chromatographed on silica gel using methylene chlorideas eluent to afford the title product as a yellow solid (9.1 g).

[0167]¹H NMR (CDCl₃) δ 1.81 (s, 3H), 7.16 (s, 1H), 7.51 (m, 2H), 7.98(d, 2H), 8.56 (d, 1H).

Step F: Preparation of3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0168] To a solution of the benzoxazinone product of Step E (6.21 g,15.21 mmol) in tetahydrofuran (100 mL) was added isopropylamine (4.23 g,72.74 mmol) and the reaction mixture was then heated to 60° C., stirredfor 1 hour and then cooled to room temperature. The tetrahydrofuransolvent was evaporated under reduced pressure, and the residual solidwas purified by chromatography on silica gel to afford the titlecompound, a compound of the present invention, as a white solid (5.05 g)melting at 173-175° C.

[0169]¹H NMR (CDCl₃) δ 1.23 (d, 6H), 2.18 (s, 3H), 4.21 (m, 1H), 5.97(d, 1H), 7.01 (m, 1H), 7.20 (s, 1H), 7.24 (s, 1H), 7.41 (d, 1H), 7.83(d, 1H), 8.43 (d, 1H), 10.15 (br s, 1H).

EXAMPLE 9 Preparation of3-Chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0170] To a solution of the benzoxazinone product of Example 8, Step E(6.32 g, 15.47 mmol) in tetrahydrofuran (50 mL) was added methylamine(2.0 M solution in THF, 38 mL, 77.38 mmol), and the reaction mixture washeated to 60° C., stirred for 1 hour and then cooled to roomtemperature. The tetrahydrofuran solvent was evaporated under reducedpressure, and the residual solid was purified by chromatography onsilica gel to afford the title compound, a compound of the presentinvention, as a white solid (4.57 g) melting at 225-226° C.

[0171]¹H NMR (CDCl₃) δ 2.15 (s, 3H), 2.93 (s, 3H), 6.21 (d, 1H), 7.06(s, 1H), 7.18 (s, 1H), 7.20 (s, 1H), 7.42 (m, 1H), 7.83 (d, 1H), 8.42(d, 1H), 10.08 (br s, 1H).

EXAMPLE 10 Preparation of3-Bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideStep A: Preparation of 3-Bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide

[0172] To a solution of N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol)in dry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solutionof n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) whilemaintaining the temperature below −60° C. A thick solid formed duringthe addition. Upon completion of the addition the reaction mixture wasmaintained for an additional 15 minutes, after which time a solution of1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150mL) was added dropwise while maintaining the temperature below −70° C.The reaction mixture turned a clear orange; stirring was continued foran additional 15 minutes. The −78° C. bath was removed and the reactionwas quenched with water (600 mL). The reaction mixture was extractedwith methylene chloride (4×), and the organic extracts were dried overmagnesium sulfate and concentrated. The crude product was furtherpurified by chromatography on silica gel using methylene chloride/hexane(50:50) as eluent to afford the title product as a clear colorless oil(57.04 g).

[0173]¹H NMR (CDCl₃) δ 3.07 (d, 6H), 6.44 (m, 1H), 7.62 (m, 1H).

Step B: Preparation of 3-Bromopyrazole

[0174] To trifluoroacetic acid (70 mL) was slowly added thebromopyrazole product (57.04 g) from Step A. The reaction mixture wasstirred at room temperature for 30 minutes and then concentrated atreduced pressure. The residue was taken up in hexane, insoluble solidswere filtered off, and the hexane was evaporated to afford the crudeproduct as an oil. The crude product was further purified bychromatography on silica gel using ethyl acetate/dichloromethane (10:90)as eluent to afford an oil. The oil was taken up in dichloromethane,neutralized with aqueous sodium bicarbonate solution, extracted withmethylene chloride (3×), dried over magnesium sulfate and concentratedto afford the title product as a white solid (25.9 g), m.p. 61-64° C.

[0175]¹H NMR (CDCl₃) δ 6.37 (d, 1H), 7.59 (d, 1H), 12.4 (br s, 1H).

Step C: Preparation of 2-(3-Bromo-1H-pyrazol-1-yl)-3-chloropyridine

[0176] To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dryN,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352mmol), and the reaction mixture was heated to 125° C. for 18 hours. Thereaction mixture was cooled to room temperature and poured into icewater (800 mL). A precipitate formed. The precipitated solids werestirred for 1.5 hrs, filtered and washed with water (2×100 mL). Thesolid filter cake was taken up in methylene chloride and washedsequentially with water, 1N hydrochloric acid, saturated aqueous sodiumbicarbonate solution, and brine. The organic extracts were then driedover magnesium sulfate and concentrated to afford 39.9 g of a pinksolid. The crude solid was suspended in hexane and stirred vigorouslyfor 1 hr. The solids were filtered, washed with hexane and dried toafford the title product as an off-white powder (30.4 g) determined tobe >94% pure by NMR. This material was used without further purificationin Step D.

[0177]¹H NMR (CDCl₃) δ 6.52 (s, 1H), 7.30 (dd, 1H), 7.92 (d, 1H), 8.05(s, 1H), 8.43 (d, 1H).

Step D: Preparation of3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid

[0178] To a solution of the pyrazole product from Step C (30.4 g, 118mmol) in dry tetrahydrofuran (250 mL) at −76° C. was added dropwise asolution of lithium diisopropylamide (118 mmol) in tetrahydrofuran atsuch a rate as to maintain the temperature below −71° C. The reactionmixture was stirred for 15 minutes at −76° C., and carbon dioxide wasthen bubbled through for 10 minutes, causing warming to −57° C. Thereaction mixture was warmed to −20° C. and quenched with water. Thereaction mixture was concentrated and then taken up in water (1 L) andether (500 mL), and then aqueous sodium hydroxide solution (1 N, 20 mL)was added. The aqueous extracts were washed with ether and acidifiedwith hydrochloric acid. The precipitated solids were filtered, washedwith water and dried to afford the title product as a tan solid (27.7g). (Product from another run following similar procedure melted at200-201° C.)

[0179]¹H NMR(DMSO-d₆) δ 7.25 (s, 1H), 7.68 (dd, 1H), 8.24 (d, 1H), 8.56(d, 1H).

Step E: Preparation of2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one

[0180] A procedure analogous to that of Example 6, Step D was used toconvert the pyrazolecarboxylic acid product from Example 10, Step D (1.5g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (0.92 g, 4.96mmol) to the title product as a solid (1.21 g).

[0181]¹H NMR (CDCl₃) δ 2.01 (s, 3H), 7.29 (s, 1H), 7.42 (d, 1H), 7.95(d, 1H), 8.04 (m, 1H), 8.25 (s, 1H), 8.26 (d, 1H).

Step F: Preparation of3-Bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0182] To a solution of the benzoxazinone product of Step E (0.20 g,0.44 mmol) in tetrahydrofuran was added isopropylamine (0.122 mL, 1.42mmol), and the reaction mixture was heated to 60° C. for 90 minutes andthen cooled to room temperature. The tetrahydrofuran solvent wasevaporated under reduced pressure, and the residual solid was trituratedwith ether, filtered, and dried to afford the title compound, a compoundof the present invention, as a solid (150 mg), m.p. 159-161° C.

[0183]¹H NMR (CDCl₃) δ 1.22 (d, 6H), 2.19 (s, 3H), 4.21 (m, 1H), 5.99(m, 1H), 7.05 (m, 1H), 7.22 (m, 2H), 7.39 (m, 1H), 7.82 (d, 1H), 8.41(d, 1H).

EXAMPLE 11 Preparation of3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide

[0184] To a solution of the benzoxazinone product of Example 10, Step E(0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 Msolution in THF, 0.514 mL, 1.02 mmol), and the reaction mixture washeated to 60° C. for 90 minutes and then cooled to room temperature. Thetetrahydrofuran solvent was evaporated under reduced pressure, and theresidual solid was triturated with ether, filtered, and dried to affordthe title compound, a compound of the present invention, as a solid (40mg), m.p. 162-164° C.

[0185]¹H NMR(CDCl₃) δ 2.18 (s, 3H), 2.95 (s, 3H), 6.21 (m, 1H), 7.10 (s,1H), 7.24 (m, 2H), 7.39 (m, 1H), 7.80 (d, 1H), 8.45 (d, 1H).

[0186] The following Example 12 illustrates an alternative preparationof 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid,which can be used to prepare, for example,3-chloro-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideand3-chloro-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 8 and 9.

EXAMPLE 12 Preparation of3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid Step A:Preparation of Ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (alternativelynamed ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate)

[0187] A 2-L four-necked flask equipped with a mechanical stirrer,thermometer, addition funnel, reflux condenser, and nitrogen inlet wascharged with absolute ethanol (250 mL) and an ethanolic solution ofsodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated toreflux at about 83° C. It was then treated with3-chloro-2(1H)-pyridinone hydrazone (68.0 g, 0.474 mol). The mixture wasre-heated to reflux over a period of 5 minutes. The yellow slurry wasthen treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over aperiod of 5 minutes. The reflux rate increased markedly during theaddition. By the end of the addition all of the starting material haddissolved. The resulting orange-red solution was held at reflux for 10minutes. After being cooled to 65° C., the reaction mixture was treatedwith glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. Themixture was diluted with water (650 mL), causing the precipitate todissolve. The orange solution was cooled in an ice bath. Product beganto precipitate at 28° C. The slurry was held at about 2° C. for 2 hours.The product was isolated via filtration, washed with aqueous ethanol(40%, 3×50 mL), and then air-dried on the filter for about 1 hour. Thetitle product compound was obtained as a highly crystalline, lightorange powder (70.3 g, 55% yield). No significant impurities wereobserved by ¹H NMR.

[0188]¹H NMR (DMSO-d₆) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20(q, 2H), 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18(s, 1H).

Step B: Preparation of Ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-chloro-2-pyrazoline-5-carboxylate)

[0189] To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was chargedacetonitrile (1000 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Step A) (91.0 g, 0.337 mol) and phosphorus oxychloride (35.0mL, 0.375 mol). Upon adding the phosphorus oxychloride, the mixtureself-heated from 22 to 25° C. and a precipitate formed. The light-yellowslurry was heated to reflux at 83° C. over a period of 35 minutes,whereupon the precipitate dissolved. The resulting orange solution washeld at reflux for 45 minutes, whereupon it had become black-green. Thereflux condenser was replaced with a distillation head, and 650 mL ofsolvent was removed by distillation. A second 2-L four-necked flaskequipped with a mechanical stirrer was charged with sodium bicarbonate(130 g, 1.55 mol) and water (400 mL). The concentrated reaction mixturewas added to the sodium bicarbonate slurry over a period of 15 minutes.The resulting, two-phase mixture was stirred vigorously for 20 minutes,at which time gas evolution had ceased. The mixture was diluted withdichloromethane (250 mL) and then was stirred for 50 minutes. Themixture was treated with Celite® 545 diatomaceous earth filter aid (11g) and then filtered to remove a black, tarry substance that inhibitedphase separation. Since the filtrate was slow to separate into distinctphases, it was diluted with dichloromethane (200 mL) and water (200 mL)and treated with more Celite® 545 (15 g). The mixture was filtered, andthe filtrate was transferred to a separatory funnel. The heavier, deepgreen organic layer was separated. A rag layer (50 mL) was refilteredand then added to the organic layer. The organic solution (800 mL) wastreated with magnesium sulfate (30 g) and silica gel (12 g), and theslurry was stirred magnetically for 30 minutes. The slurry was filteredto remove the magnesium sulfate and silica gel, which had become deepblue-green. The filter cake was washed with dichloromethane (100 mL).The filtrate was concentrated on a rotary evaporator. The productconsisted of dark amber oil (92.0 g, 93% yield). The only appreciableimpurities observed by ¹H NMR were 1% starting material and 0.7%acetonitrile.

[0190]¹H NMR (D)MSO-d₆) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H),4.11 (q, 2H), 5.25 (dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step C: Preparation of Ethyl3-chloro-1(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-chloropyrazole-5-carboxylate)

[0191] A 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged with ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. the product of Step B) (95% pure, 99.5 g, 0.328 mol), acetonitrile(1000 mL) and sulfuric acid (98%, 35.0 mL, 0.661 mol). The mixtureself-heated from 22 to 35° C. upon adding the sulfuric acid. After beingstirred for several minutes, the mixture was treated with potassiumpersulfate (140 g, 0.518 mol). The slurry was heated to reflux at 84° C.for 4.5 hours. The resulting orange slurry while still warm (50-65° C.)was filtered to remove a fine, white precipitate. The filter cake waswashed with acetonitrile (50 mL). The filtrate was concentrated to about500 mL on a rotary evaporator. A second 2-L four-necked flask equippedwith a mechanical stirrer was charged with water (1250 mL). Theconcentrated reaction mass was added to the water over a period of about5 minutes. The product was isolated via filtration, washed with aqueousacetonitrile (25%, 3×125 nL), washed once with water (100 mL), and thendried overnight in vacuo at room temperature. The product consisted of acrystalline, orange powder (79.3 g, 82% yield). The only appreciableimpurities observed by ¹H NMR were about 1.9% water and 0.6%acetonitrile.

[0192] 1H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.31 (s, 1H), 7.71(dd, 1H), 8.38 (d, 1H), 8.59 (d, 1H).

Step D: Preparation of3-Chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid(alternatively named1-(3-chloro-²-pyridinyl)-3-chloropyrazole-5-carboxylic acid)

[0193] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged with ethyl3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. theproduct of Step C) (97.5% pure, 79.3 g, 0.270 mol), methanol (260 mL),water (140 mL) and sodium hydroxide pellets (13.0 g, 0.325 mol). Uponadding the sodium hydroxide the mixture self-heated from 22 to 35° C.,and the starting material began to dissolve. After being stirred for 45minutes under ambient conditions, all of the starting material haddissolved. The resulting deep orange-brown solution was concentrated toabout 250 mL on a rotary evaporator. The concentrated reaction mixturewas then diluted with water (400 mL). The aqueous solution was extractedwith ether (200 mL). Then the aqueous layer was transferred to a 1-LErlenmeyer flask equipped with a magnetic stirrer. The solution wastreated dropwise with concentrated hydrochloric acid (36.0 g, 0.355 mol)over a period of about 10 minutes. The product was isolated viafiltration, reslurried with water (2×200 mL), cover washed once withwater (100 mL) and then air-dried on the filter for 1.5 hours. Theproduct consisted of a crystalline, light brown powder (58.1 g, 83%yield). About 0.7% ether was the only appreciable impurity observed by¹H NMR.

[0194]¹H NMR (DMSO-d₆) δ 7.20 (s, 1H), 7.68 (dd, 1H), 8.25 (d, 1H), 8.56(d, 1H), 13.95 (br, s, 1H).

[0195] The following Example 13 illustrates an alternative preparationof 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, whichcan be used to prepare, for example,3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideand3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 10 and 11.

EXAMPLE 13 Preparation of3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid Step A1:Preparation of Ethyl3-bromo-1-(3-chloro-2-pyridinyl)4,5-dihydro-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-bromo-2-pyrazoline-5-carboxylate) usingphosphorus oxybromide

[0196] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged withacetonitrile (400 mL), ethyl2-(3-chloro-2-Pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 12, Step A) (50.0 g, 0.185 mol) and phosphorusoxybromide (34.0 g, 0.119 mol). The orange slurry was heated to refluxat 83° C. over a period of 20 minutes. The resulting turbid, orangesolution was held at reflux for 75 minutes, at which time a dense, tan,crystalline precipitate had formed. The reflux condenser was replacedwith a distillation head, and a cloudy, colorless distillate (300 mL)was collected. A second 1-L four-necked flask equipped with a mechanicalstirrer was charged with sodium bicarbonate (45 g, 0.54 mol) and water(200 mL). The concentrated reaction mixture was added to the sodiumbicarbonate slurry over a period of 5 minutes. The resulting two-phasemixture was stirred vigorously for 5 minutes, at which time gasevolution had ceased. The mixture was diluted with dichloromethane (200mL) and then was stirred for 75 minutes. The mixture was treated with 5g of Celite® 545 diatomaceous filter aid and then filtered to remove abrown, tarry substance. The filtrate was transferred to a separatoryfunnel. The brown organic layer (400 mL) was separated and then wastreated with magnesium sulfate (15 g) and Darco® G60 activated charcoal(2.0 g). The resulting slurry was stirred magnetically for 15 minutesand then filtered to remove the magnesium sulfate and charcoal. Thegreen filtrate was treated with silica gel (3 g) and stirred for severalminutes. The deep blue-green silica gel was removed by filtration, andthe filtrate was concentrated on a rotary evaporator. The productconsisted of a light amber oil (58.6 g, 95% yield), which crystallizedupon standing. The only appreciable impurity observed by ¹H NMR was 0.3%acetonitrile.

[0197]¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H),4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step A2: Preparation of Ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateusing phosphorus pentabromide

[0198] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged withacetonitrile (330 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 12, Step A) (52.0 g, 0.193 mol), and phosphoruspentabromide (41.0 g, 0.0952 mol). The orange slurry was heated toreflux at 84° C. over a period of 20 minutes. The resulting brick-redmixture was held at reflux for 90 minutes, at which time a dense tancrystalline precipitate had formed. The reflux condenser was replacedwith a distillation head, and a cloudy, colorless distillate (220 mL)was collected. A second 1-L four-necked flask equipped with a mechanicalstirrer was charged with sodium bicarbonate (40 g, 0.48 mol) and water(200 mL). The concentrated reaction mixture was added to the sodiumbicarbonate slurry over a period of 5 minutes. The resulting, two-phasemixture was stirred vigorously for 10 minutes, at which time gasevolution had ceased. The mixture was diluted with dichloromethane (200mL) and then was stirred for 10 minutes. The mixture was treated withCelite® 545 diatomaceous filter aid (5 g) and then filtered to remove apurple, tarry substance. The filter cake was washed with dichloromethane(50 mL). The filtrate was transferred to a separatory funnel. Thepurple-red organic layer (400 mL) was separated and then was treatedwith magnesium sulfate (15 g) and Darco® G60 activated charcoal (2.2 g).The slurry was stirred magnetically for 40 minutes. The slurry wasfiltered to remove the magnesium sulfate and charcoal. The filtrate wasconcentrated on a rotary evaporator. The product consisted of a darkamber oil (61.2 g, 95% yield), which crystallized upon standing. Theonly appreciable impurity observed by ¹H NMR was 0.7% acetonitrile.

[0199]¹H NMR (DMSO-d₆) δ 1.15 (t, 3H), 3.29 (dd, 1H), 3.60 (dd, 1H),4.11 (q, 2H), 5.20 (dd, 1H), 6.99 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step B: Preparation of Ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate(alternatively named ethyl1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylate)

[0200] A 1-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was charged with ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. the product of Steps A1 and A2) (40.2 g, 0.121 mol), acetonitrile(300 mL) and sulfuric acid (98%, 13.0 mL, 0.245 mol). The mixtureself-heated from 22 to 36° C. upon adding the sulfuric acid. After beingstirred for several minutes, the mixture was treated with potassiumpersulfate (48.0 g, 0.178 mol). The slurry was heated to reflux at 84°C. for 2 hours. The resulting orange slurry while still warm (50-65° C.)was filtered to remove a white precipitate. The filter cake was washedwith acetonitrile (2×50 mL). The filtrate was concentrated to about 200mL on a rotary evaporator. A second 1-L four-necked flask equipped witha mechanical stirrer was charged with water (400 mL). The concentratedreaction mass was added to the water over a period of about 5 minutes.The product was isolated via filtration, washed sequentially withaqueous acetonitrile (20%, 100 mL) and water (75 mL), and was thenair-dried on the filter for 1 hour. The product consisted of acrystalline, orange powder (36.6 g, 90% yield). The only appreciableimpurities observed by 1H NMR were about 1% of an unknown and 0.5%acetonitrile.

[0201]¹H NMR (DMSO-d₆) δ 1.09 (t, 3H), 4.16 (q, 2H), 7.35 (s, 1H), 7.72(dd, 1H), 8.39 (d, 1H), 8.59 (d, 1H).

Step C: Preparation of3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid(alternatively named1-(3-chloro-2-pyridinyl)-3-bromopyrazole-5-carboxylic acid)

[0202] A 300-mL four-necked flask equipped with a mechanical stirrer,thermometer, and nitrogen inlet was charged with ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. theproduct of Step B) (98.5% pure, 25.0 g, 0.0756 mol), methanol (75 mL),water (50 mL), and sodium hydroxide pellets (3.30 g, 0.0825 mol). Uponadding the sodium hydroxide the mixture self-heated from 29 to 34° C.and the starting material began to dissolve. After being stirred for 90minutes under ambient conditions, all of the starting material haddissolved. The resulting dark orange solution was concentrated to about90 mL on a rotary evaporator. The concentrated reaction mixture was thendiluted with water (160 mL). The aqueous solution was extracted withether (100 mL). Then the aqueous layer was transferred to a 500-mLErlenmeyer flask equipped with a magnetic stirrer. The solution wastreated dropwise with concentrated hydrochloric acid (8.50 g, 0.0839mol) over a period of about 10 minutes. The product was isolated viafiltration, reslurried with water (2×40 mL), cover washed once withwater (25 mL), and then air-dried on the filter for 2 hours. The productconsisted of a crystalline, tan powder (20.9 g, 91% yield). The onlyappreciable impurities observed by ¹H NMR were about 0.8% of an unknownand 0.7% ether.

[0203]¹H NMR (DMSO-d₆) δ 7.25 (s, 1H), 13.95 (br s, 1H), 8.56 (d, 1H),8.25 (d, 1H), 7.68 (dd, 1H).

[0204] The following Example 14 illustrates an alternative preparationof ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate,which can be used to prepare, for example, ethyl3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. productof Example 13, Step B).

EXAMPLE 14 Preparation of Ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylatefrom ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateusing hydrogen bromide

[0205] Hydrogen bromide was passed through a solution of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. product of Example 12, Step B) (8.45 g, 29.3 mmol) indibromomethane (85 mL). After 90 minutes the gas flow was terminated,and the reaction mixture was washed with aqueous sodium bicarbonatesolution (100 mL). The organic phase was dried and evaporated underreduced pressure to give the title product as an oil (9.7 g, 99% yield),which crystallized on standing.

[0206]¹H NMR (CDCl₃) δ 1.19 (t, 3H), 3.24 (½ of AB in ABX pattern,J=9.3, 17.3 Hz, 1H), 3.44(½ of AB in ABX pattern, J=11.7, 17.3 Hz, 1H),4.18 (q, 2H), 5.25 (X of ABX, 1H, J=9.3, 11.9 Hz), 6.85 (dd, J=4.7, 7.7Hz, 1H), 7.65 (dd, J=1.6, 7.8 Hz, 1H), 8.07 (dd, J=1.6, 4.8Hz, 1H).

[0207] The following Example 15 illustrates the preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate,which can be used to prepare ethyl3-bromo-1-(3-chloro-2-pyridinyl)4,5-dihydro-1H-pyrazole-5-carboxylate byprocedures similar to that described in Example 14.

EXAMPLE 15 Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

[0208] Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixtureof ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e.the product of Example 12, Step A) (10.0 g, 37.1 mmol) andp-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g,1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. Thereaction mixture was then allowed to warm to room temperature and wasstirred overnight. The mixture was then diluted with dichloromethane(200 mL) and washed with water (3×70 mL). The organic phase was driedand evaporated to leave the title product as an oil (13.7 g, 87% yield),which slowly formed crystals. Product recrystallized from ethylacetate/hexanes melted at 99.5-100° C.

[0209] IR (nujol) ν 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191,1178, 1084, 1027, 948, 969, 868, 845 cm⁻¹.

[0210]¹H NMR (CDCl₃) δ 1.19 (t, 3H), 2.45 (s, 3H), 3.12 (½ of AB in ABXpattern, J=17.3, 9 Hz, 1H), 3.33 (½ of AB in ABX pattern, J=17.5, 11.8Hz, 1H), 4.16 (q, 2H), 5.72 (X of ABX, J=9, 11.8 Hz, 1H), 6.79 (dd,J=4.6, 7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.56 (dd, J=1.6, 7.8 Hz,1H), 7.95 (d, J=8.4 Hz, 2H), 8.01 (dd, J=1.4, 4.6 Hz, 1H).

EXAMPLE 16 Preparation ofN-[4-Chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamideStep A: Preparation of Ethyl1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate

[0211] To a suspension of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. productof Example 12, Step A) (27 g, 100 mmol) stirred in dry acetonitrile (200mL) was added sulfuric acid (20 g, 200 mmol) in one portion. Thereaction mixture thinned to form a pale green, nearly clear solutionbefore thickening again to form a pale yellow suspension. Potassiumpersulfate (33 g, 120 mmol) was added in one portion, and then thereaction mixture was heated at gentle reflux for 3.5 hours. Aftercooling using an ice bath, a precipitate of white solid was removed byfiltration and discarded. The filtrate was diluted with water (400 mL)and then extracted three times with ethyl ether (700 mL total).Concentration of the combined ether extracts to a reduced volume (75 mL)caused precipitation of an off-white solid (3.75 g), which was collectedby filtration. The ether mother liquor was further concentrated to yielda second crop of an off-white precipitate (4.2 g), which was alsocollected by filtration. An off-white solid also precipitated from theaqueous phase; this solid (4.5 g) was collected by filtration to providea combined total of 12.45 g of the title compound.

[0212]¹H NMR (DMSO-d₆) δ 1.06 (t, 3H), 4.11 (q, 2H), 6.34 (s, 1H), 7.6(t, 1H),8.19 (d, 1H), 8.5 (d, 1H), 10.6 (s, 1H).

Step B: Preparation of Ethyl1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate

[0213] To a suspension of ethyl1-(3-chloro-2-pyridinyl)-2,3-dihydro-3-oxo-1H-pyrazole-5-carboxylate(i.e. product of Step A) (0.8 g, 3 mmol) stirred in dry acetonitrile (15mL) at −5° C. was added potassium carbonate (0.85 g, 6.15 mmol). Thesuspension was stirred for 15 minutes at 20 ° C. The stirred suspensionwas then cooled to 5° C., and 2,2,2-trifluoro-ethyltrifluoromethanesulfonate (0.8 g, 3.45 mmol) was added dropwise. Thereaction mixture was warmed to room temperature and then heated toreflux, at which time thin layer chromatography showed the reaction tobe complete. Water (25 mL) was added to the reaction mixture, which wasthen extracted with ethyl ether. The ether extract was dried overmagnesium sulfate and concentrated to yield the title product compound(1.05 g) as a pale yellow oil.

[0214]¹H NMR (CDCl₃) δ 1.21 (t, 3H), 4.20 (q, 2H), 4.63 (q, 2H), 6.53(s, 1H), 7.4 (t, 1H), 7.9 (d, 1H), 8.5 (d, 1H).

Step C: Preparation of1-(3-Chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylicacid

[0215] To a stirred solution of ethyl1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylate(i.e. product of Step B) (0.92 g, 2.8 mmol) in methanol (15 mL) wasadded water (5 mL), which caused the reaction mixture to become cloudy.An aqueous solution of sodium hydroxide (50%, 1.5 g, 19.2 mmol) wasadded dropwise, and the reaction mixture was stirred at room temperaturefor 30 minutes, during which time the reaction mixture became againclear. Water (20 mL) was added and the reaction mixture was extractedwith ethyl ether, which was discarded. The aqueous phase was acidifiedto pH 2 using concentrated hydrochloric acid and then extracted withethyl acetate (50 mL). The ethyl acetate extract, which was washed withwater (20 mL) and brine (20 mL), dried over magnesium sulfate andconcentrated to give the title compound, isolated as a white solid (0.8g).

[0216]¹H NMR (DMSO-d₆) δ 4.9 (q, 2H), 6.75 (s, 1H), 7.6 (t, 1H), 8.2 (d,1H), 8.55 (d, 1H), 13.7 (bs, 1H).

Step D: Preparation of6-Chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione

[0217] To a suspension of 2-amino-3-methyl-5-chlorobenzoic acid (i.e.product of Example 6, Step A) (97 g, 520 mmol) stirred in dry dioxane(750 mL) at room temperature, trichloromethyl chloroformate (63 g, 320mmol) was added dropwise. The reaction mixture exothermically warmedslowly to 42° C., and the solid almost completely dissolved before athick suspension formed again. After the suspension was stirred atambient temperature for 2.5 hours, the title compound was isolated byfiltration, washed with ethyl ether, and dried to yield the titleproduct compound, obtained as a white solid (98 g).

[0218]¹H NMR (DMSO-d₆) δ 2.3 (s, 3H), 7.70 (s, 1H), 7.75 (s, 11H), 11.2(s, 1H).

Step E: Preparation of6-Chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0219] To a suspension of1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylicacid (i.e. product of Step C) (7.9 g, 24mmol) stirred in dichloromethane(100 mL) was added N,N-dimethylformamide (4 drops). Oxalyl chloride(4.45 g, 35 mmol) was added dropwise over a period of 45 minutes. Theresulting solution was stirred at room temperature for 4 hours and thenconcentrated under vacuum. The isolated acid chloride was dissolved indry acetonitrile (10 mL) and added to a suspension of6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of StepD) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10mL) was added, and the solution heated at reflux 6 hours. After coolingusing an ice bath, a precipitate of white solid (9.15 g) was collected.The ¹H NMR spectrum of the collected precipitate showed peaks consistentwith the title compound and residual6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. Asmall portion of the collected precipitate was recrystallized fromacetonitrile to yield the pure title product melting at 178-180° C.

[0220]¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 4.96 (q, 2H), 7.04 (s, 1H), 7.7(t, 1H), 7.75 (s, 1H), 7.9 (s, 1H), 8.3 (d, 1H), 8.6 (d, 1H).

Step F: Preparation ofN-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-H-pyrazole-5-carboxamide

[0221] To a suspension of the6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]-8-methyl4H-3,1-benzoxazin-4-one(i.e. precipitate product of Step E) (3.53 g, 7.5 mmol) intetrahydrofuran (15 mL), methylamine (2.0 M solution in TBF, 11 mL, 22mmol) was added dropwise, and the resulting solution was stirred at roomtemperature for 45 minutes. Thin layer chromatography then showed thereaction to be complete. Ethyl ether (100 mL) was added, and thereaction mixture was stirred for 2 hours while a precipitate formed. Theprecipitate was collected by filtration and then recrystallized fromacetonitrile to yield a white solid (0.82 g). A second crop of whitesolid (0.35 g) precipitated from the acetonitrile mother liquor and wascollected by filtration. The initial ether/tetrahydrofuran mother liquorwas concentrated to dryness, and the residual solid was recrystallizedfrom acetonitrile to yield a third crop of white solid (0.95 g). Thethree crops were combined, totaling 2.12 g (after drying) of the titlecompound, a compound of the present invention, isolated as a whitesolid, melting at 195-197° C.

[0222]¹H NMR (CDCl₃) δ 2.18 (s, 3H), 2.92 (d, 3H), 4.66 (q, 2H), 6.15(q, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.8 (d,1H), 8.45 (d, 1H), 10.0 (s, 1H).

[0223] The following Example 17 illustrates an alternative preparationof 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid, which can be used to prepare, for example,1-(3-chloro-2-pyridinyl)-N-[2-methyl-6-[[(1-methylethyl)amino]carbonyl]-phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide,by further steps illustrated in Examples 4.

EXAMPLE 17 Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid Step A: Preparation of 3-chloro-2(1H)-pyridinone(2,2,2-trifluoro-1-methylethylidene)hydrazone

[0224] 1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to3-chloro-2(1H)-pyridinone hydrazone (alternatively named(3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. Afterthe addition was complete, the mixture was stirred for about 10 minutes.The solvent was removed under reduced pressure and the mixturepartitioned between ethyl acetate (100 mL) and saturated aqueous sodiumcarbonate solution (100 mL). The organic layer was dried and evaporatedChromatography on silica gel (eluted with ethyl acetate) gave theproduct as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (aftercrystallization from ethyl acetate/hexanes).

[0225] IR (nujol) ν 1629, 1590, 1518, 1403, 1365, 1309, 1240, 1196,1158, 1100, 1032, 992, 800 cm⁻¹. ¹H NMR (CDCl₃) δ 2.12 (s, 3H),6.91−6.86 (m, 1H), 7.64−7.61 (m, 1H), 8.33−8.32 (m, 2H). MS nm/z 237(M⁺).

Step B: Preparation of ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazide(Alternatively Named ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methylethylidene)hydrazine)

[0226] Triethylamine (20.81 g, 0.206 mol) was added to3-chloro-2(1H)-pyridinone (2,2,2-trifluoro-1-methylethylidene)hydrazone(i.e. the product of Step A) (32.63 g, 0.137 mol) in dichloromethane (68mL) at 0° C. Ethyl chlorooxoacetate (18.75 g, 0.137 mol) indichloromethane (69 mL) was added dropwise to the mixture at 0° C. Themixture was allowed to warm to 25° C. over about 2 hours. The mixturewas cooled to 0° C. and a further portion of ethyl chlorooxoacetate(3.75 g, 27.47 mmol) in dichloromethane (14 mL) was added dropwise.After about an additional 1 hour, the mixture was diluted withdichloromethane (about 450 mL), and the mixture was washed with water(2×150 mL). The organic layer was dried and evaporated. Chromatographyon silica gel (eluted with 1:1 ethyl acetate-hexanes) gave the productas a solid (42.06 g, 90% yield), m.p. 73.0-73.5° C. (aftercrystallization from ethyl acetate/hexanes).

[0227] IR (nujol) ν 1751, 1720, 1664, 1572, 1417, 1361, 1330, 1202,1214, 1184, 1137, 1110, 1004, 1043, 1013, 942, 807, 836 cm⁻¹. ¹H NMR(DMSO-d₆, 115° C.) 1.19 (t, 3H), 1.72 (br s, 3H), 4.25 (q, 2H), 7.65(dd, J=8.3, 4.7 Hz, 1H), 8.20 (dd, J=7.6, 1.5 Hz, 1H), 8.55 (d, J=3.6Hz, 1H). MS m/z 337 (M⁺).

Step C: Preparation of ethyl1-(³-chloro-²-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0228] Ethyl hydrogen ethanedioate(3-chloro-2-pyridinyl)(2,2,2-trifluoro-1-methyl-ethylidene)hydrazide(i.e. the product of Step B) (5 g, 14.8 mmol) in dimethyl sulfoxide(25mL) was added to tetrabutylammonium fluoride hydrate (10 g) indimethyl sulfoxide (25 mL) over 8 hours. When the addition was complete,the mixture was poured into acetic acid (3.25 g) in water (25 mL). Afterstirring at 25° C. overnight, the mixture was then extracted withtoluene (4×25 mL), and the combined toluene extracts were washed withwater (50 mL), dried and evaporated to give a solid. Chromatography onsilica gel (eluted with 1:2 ethyl acetate-hexanes) gave the product as asolid (2.91 g, 50% yield, containing about 5% of3-chloro-2(1H)-pyridinone(2,2,2-trifluoro-1-methylethylidene)hydrazone), m.p. 78-78.5° C. (afterrecrystallization from ethyl acetate/hexanes).

[0229] IR (nujol) ν 3403, 1726, 1618, 1582, 1407, 1320, 1293, 1260,1217, 1187, 1150, 1122, 1100, 1067, 1013, 873, 829 cm⁻¹. ¹H NMR (CDCl₃)δ 1.19 (s, 3H), 3.20 (½ of ABZ pattern, J=18 Hz, 1H), 3.42 (½ of ABZpattern, J=18 Hz, 1H), 4.24 (q, 2H), 6.94 (dd, J=7.9,4.9 Hz, 1H), 7.74(dd, J=7.7, 1.5 Hz, 1H), 8.03 (dd, J=4.7, 1.5 Hz, 1H). MS m/z 319(M⁺).

Step D: Preparation of ethyl1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0230] Sulfuric acid (concentrated, 2 drops) was added to ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-5-hydroxy-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(i.e. the product of Step C) (1 g, 2.96 mmol) in acetic acid (10 mL) andthe mixture was warmed to 65° C. for about 1 hour. The mixture wasallowed to cool to 25° C. and most of the acetic acid was removed underreduced pressure. The mixture was partitioned between saturated aqueoussodium carbonate solution (100 mL) and ethyl acetate (100 mL). Theaqueous layer was further extracted with ethyl acetate (100 mL). Thecombined organic extracts were dried and evaporated to give the productas an oil (0.66 g, 77% yield).

[0231] IR (neat) ν 3147, 2986, 1734, 1577, 1547, 1466, 1420, 1367, 1277,1236, 1135, 1082, 1031, 973, 842, 802 cm⁻¹. ¹H NMR (CDCl₃) δ 1.23 (t,3H), 4.25 (q, 2H), 7.21 (s, 1H), 7.48 (dd, J=8.1, 4.7 Hz, 1H), 7.94 (dd,J=6.6, 2 Hz, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H). MS m/z 319 (M⁺).

Step E: Preparation of1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid

[0232] Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) wasadded to ethyl1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(i.e. the product of Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL).After about 30 minutes, the solvent was removed under reduced pressure,and the mixture was dissolved in water (40 mL). The solution was washedwith ethyl acetate (20 mL). The aqueous layer was acidified withconcentrated hydrochloric acid and was extracted with ethyl acetate(3×20 mL). The combined extracts were dried and evaporated to give theproduct as a solid (0.53 g, 93% yield), m.p. 178-179° C. (aftercrystallization from hexanes-ethyl acetate).

[0233] IR (nujol) ν 1711, 1586, 1565, 1550, 1440, 1425, 1292, 1247,1219, 1170, 1135, 1087, 1059, 1031, 972, 843, 816 cm⁻¹. ¹H NMR (DMSO-d₆)δ 7.61 (s, 1H), 7.77 (m, 1H), 8.30 (d, 1H), 8.60 (s, 1H).

[0234] Examples 18 and 19 illustrate alternatives to reaction conditionsdescribed in Example 10, Step E and Example 8, Step E, respectively.

EXAMPLE 18 Preparation of2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin4-one

[0235] Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolvedin acetonitrile (10 mL), and the mixture was cooled to −5° C. A solutionof 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the pyrazolecarboxylic acid product of Example 10, Step D) (3.02 g, 10mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) wasadded dropwise over 5 minutes at −5 to 0° C. A slurry formed during theaddition. The mixture was stirred 5 minutes at this temperature, andthen a mixture of 2-amino-3-methyl-5-chlorobenzoic acid (i.e. theproduct of Example 6 Step A) (1.86 g, 10 mmol) and pyridine (2.8 mL, 2.7g, 35 mmol) in acetonitrile (10 mL) was added, rinsing with moreacetonitrile (5 mL). The mixture was stirred 15 minutes at −5 to 0° C.,and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) inacetonitrile (5 mL) was added dropwise over 5 minutes at a temperatureof −5 to 0° C. The reaction mixture was stirred 15 minutes more at thistemperature, then allowed to warm slowly to room temperature, andstirred 4 h. Water (20 mL) was added dropwise, and the mixture wasstirred 15 minutes. Then the mixture was filtered, and the solids werewashed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3mL), and dried under nitrogen to afford the title product as a lightyellow powder, 4.07 g (90.2% crude yield), melting at 203-205° C. HPLCof the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25cm, eluent 25-95% acetonitrile/ pH 3 water) showed a major peakcorresponding to the title compound and having 95.7% of totalchromatogram peak area.

[0236]¹H NMR (DMSO-d₆) δ 1.72 (s, 3H) 7.52 (s, 1H), 7.72-7.78 (m, 2H),7.88 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

EXAMPLE 19 Preparation of6-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one

[0237] Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolvedin acetonitrile (10 mL), and the mixture was cooled to −5° C. A solutionof 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e.the carboxylic acid product of Example 8, Step D) (2.58 g, 10 mmol) andpyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was addeddropwise over 5 minutes at −5 to 0° C. A slurry formed during theaddition. The mixture was stirred 5 minutes at this temperature, andthen 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product fromExample 6, Step A) (1.86 g, 10 mmol) was added all at once. Then asolution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL)was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to0° C. The reaction mixture was stirred 15 minutes at this temperature,then allowed to warm slowly to room temperature, and stirred 4 h. Water(15 mL) was added dropwise, and the mixture was stirred 15 minutes. Thenthe mixture was filtered, and the solids were washed with 2:1acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and driedunder nitrogen to afford the title product as a pale yellow powder, 3.83g (94.0% crude yield), melting at 199-201° C. HPLC of the product usinga Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95%acetonitrile/pH 3 water) showed a major peak corresponding to the titlecompound and having 97.8% of total chromatogram peak area.

[0238]¹H NMR (DMSO-d₆) δ 1.72 (s, 3H), 7.48 (s, 1H), 7.74-7.80 (m, 2H),7.87 (m, 1H), 8.37 (dd, 1H), 8.62 (dd, 1H).

[0239] By the procedures described herein together with methods known inthe art, the following compounds of Tables 1-6 can be prepared. Thefollowing abbreviations are used in the Tables which follow: t meanstertiary, s means secondary, n means normal, i means iso, Me meansmethyl, Et means ethyl Pr means propyl i-Pr means isopropyl, and Bumeans butyl. TABLE 1

R³ R⁴ Q X Y Z R³ R⁴ Q X Y Z i-Pr Me NMe N CH CCF₃ i-Pr Me NMe N CH CC₂F₅i-Pr Cl NMe N CH CCF₃ i-Pr Cl NMe N CH CC₂F₅ i-Pr Br NMe N CH CCF₃ i-PrBr NMe N CH CC₂F₅ i-Pr I NMe N CH CCF₃ i-Pr I NMe N CH CC₂F₅ i-Pr F NMeN CH CCF₃ i-Pr F NMe N CH CC₂F₅ i-Pr H NMe N CH CCF₃ i-Pr H NMe N CHCC₂F₅ i-Pr Et NMe N CH CCF₃ i-Pr Et NMe N CH CC₂F₅ i-Pr Me NEt N CH CCF₃t-Bu Me NMe N CH CCF₃ i-Pr Cl NEt N CH CCF₃ t-Bu Cl NMe N CH CCF₃ i-PrBr NEt N CH CCF₃ t-Bu Br NMe N CH CCF₃ i-Pr I NEt N CH CCF₃ t-Bu I NMe NCH CCF₃ i-Pr F NEt N CH CCF₃ t-Bu F NMe N CH CCF₃ i-Pr H NEt N CH CCF₃t-Bu H NMe N CH CCF₃ i-Pr Et NEt N CH CCF₃ t-Bu Et NMe N CH CCF₃

[0240] TABLE 2

W X Y Z R³ R⁴ R⁶ R⁹ CH CH CH CH i-Pr Me CF₃ Me CH CH CH CH t-Bu Me CF₃Me CH CH CH CH i-Pr Cl CF₃ Me CH CH CH CH t-Bu Cl CF₃ Me CH CH CH CHi-Pr Br CF₃ Me CH CH CH CH t-Bu Br CF₃ Me CH CH CH CH i-Pr Me Cl Me CHCH CH CH t-Bu Me Cl Me CH CH CH CH i-Pr Cl Cl Me CH CH CH CH t-Bu Cl ClMe CH CH CH CH i-Pr Br Cl Me CH CH CH CH t-Bu Br Cl Me CH CH CH CH i-PrMe Br Me CH CH CH CH t-Bu Me Br Me CH CH CH CH i-Pr Cl Br Me CH CH CH CHt-Bu Cl Br Me CH CH CH CH i-Pr Br Br Me CH CH CH CH t-Bu Br Br Me CH CHCH CH i-Pr Me CN Me CH CH CH CH t-Bu Me CN Me CH CH CH CH i-Pr Cl CN MeCH CH CH CH t-Bu Cl CN Me CH CH CH CH i-Pr Br CN Me CH CH CH CH t-Bu BrCN Me CH CH CH CH i-Pr Me CF₃ F CH CH CH CH t-Bu Me CF₃ F CH CH CH CHi-Pr Cl CF₃ F CH CH CH CH t-Bu Cl CF₃ F CH CH CH CH i-Pr Br CF₃ F CH CHCH CH t-Bu Br CF₃ F CH CH CH CH i-Pr Me Cl F CH CH CH CH t-Bu Me Cl F CHCH CH CH i-Pr Cl Cl F CH CH CH CH t-Bu Cl Cl F CH CH CH CH i-Pr Br Cl FCH CH CH CH t-Bu Br Cl F CH CH CH CH i-Pr Me Br F CH CH CH CH t-Bu Me BrF CH CH CH CH i-Pr Cl Br F CH CH CH CH t-Bu Cl Br F CH CH CH CH i-Pr BrBr F CH CH CH CH t-Bu Br Br F CH CH CH CH i-Pr Me CN F CH CH CH CH t-BuMe CN F CH CH CH CH i-Pr Cl CN F CH CH CH CH t-Bu Cl CN F CH CH CH CHi-Pr Br CN F CH CH CH CH t-Bu Br CN F CH CH CH CH i-Pr Me CF₃ Cl CH CHCH CH t-Bu Me CF₃ Cl CH CH CH CH i-Pr Cl CF₃ Cl CH CH CH CH t-Bu Cl CF₃Cl CH CH CH CH i-Pr Br CF₃ Cl CH CH CH CH t-Bu Br CF₃ Cl CH CH CH CHi-Pr Me Cl Cl CH CH CH CH t-Bu Me Cl Cl CH CH CH CH i-Pr Cl Cl Cl CH CHCH CH t-Bu Cl Cl Cl CH CH CH CH i-Pr Br Cl Cl CH CH CH CH t-Bu Br Cl ClCH CH CH CH i-Pr Me Br Cl CH CH CH CH t-Bu Me Br Cl CH CH CH CH i-Pr ClBr Cl CH CH CH CH t-Bu Cl Br Cl CH CH CH CH i-Pr Br Br Cl CH CH CH CHt-Bu Br Br Cl CH CH CH CH i-Pr Me CN Cl CH CH CH CH t-Bu Me CN Cl CH CHCH CH i-Pr Cl CN Cl CH CH CH CH t-Bu Cl CN Cl CH CH CH CH i-Pr Br CN ClCH CH CH CH t-Bu Br CN Cl CH CH CH CH i-Pr Me CF₃ Br CH CH CH CH t-Bu MeCF₃ Br CH CH CH CH i-Pr Cl CF₃ Br CH CH CH CH t-Bu Cl CF₃ Br CH CH CH CHi-Pr Br CF₃ Br CH CH CH CH t-Bu Br CF₃ Br CH CH CH CH i-Pr Me Cl Br CHCH CH CH t-Bu Me Cl Br CH CH CH CH i-Pr Cl Cl Br CH CH CH CH t-Bu Cl ClBr CH CH CH CH i-Pr Br Cl Br CH CH CH CH t-Bu Br Cl Br CH CH CH CH i-PrMe Br Br CH CH CH CH t-Bu Me Br Br CH CH CH CH i-Pr Cl Br Br CH CH CH CHt-Bu Cl Br Br CH CH CH CH i-Pr Br Br Br CH CH CH CH t-Bu Br Br Br CH CHCH CH i-Pr Me CN Br CH CH CH CH t-Bu Me CN Br CH CH CH CH i-Pr Cl CN BrCH CH CH CH t-Bu Cl CN Br CH CH CH CH i-Pr Br CN Br CH CH CH CH t-Bu BrCN Br CH CH CH CH i-Pr Me CF₃ CN CH CH CH CH t-Bu Me CF₃ CN CH CH CH CHi-Pr Cl CF₃ CN CH CH CH CH t-Bu Cl CF₃ CN CH CH CH CH i-Pr Br CF₃ CN CHCH CH CH t-Bu Br CF₃ CN CH CH CH CH i-Pr Me Cl CN CH CH CH CH t-Bu Me ClCN CH CH CH CH i-Pr Cl Cl CN CH CH CH CH t-Bu Cl Cl CN CH CH CH CH i-PrBr Cl CN CH CH CH CH t-Bu Br Cl CN CH CH CH CH i-Pr Me Br CN CH CH CH CHt-Bu Me Br CN CH CH CH CH i-Pr Cl Br CN CH CH CH CH t-Bu Cl Br CN CH CHCH CH i-Pr Br Br CN CH CH CH CH t-Bu Br Br CN CH CH CH CH i-Pr Me CN CNCH CH CH CH t-Bu Me CN CN CH CH CH CH i-Pr Cl CN CN CH CH CH CH i-Bu ClCN CN CH CH CH CH i-Pr Br CN CN CH CH CH CH t-Bu Br CN CN CH CH CH Ni-Pr Me CF₃ Me CH CH CH N t-Bu Me CF₃ Me CH CH CH N i-Pr Cl CF₃ Me CH CHCH N t-Bu Cl CF₃ Me CH CH CH N i-Pr Br CF₃ Me CH CH CH N t-Bu Br CF₃ MeCH CH CH N i-Pr Me Cl Me CH CH CH N t-Bu Me Cl Me CH CH CH N i-Pr Cl ClMe CH CH CH N t-Bu Cl Cl Me CH CH CH N i-Pr Br Cl Me CH CH CH N t-Bu BrCl Me CH CH CH N i-Pr Me Br Me CH CH CH N t-Bu Me Br Me CH CH CH N i-PrCl Br Me CH CH CH N t-Bu Cl Br Me CH CH CH N i-Pr Br Br Me CH CH CH Nt-Bu Br Br Me CH CH CH N i-Pr Me CN Me CH CH CH N t-Bu Me CN Me CH CH CHN i-Pr Cl CN Me CH CH CH N t-Bu Cl CN Me CH CH CH N i-Pr Br CN Me CH CHCH N i-Bu Br CN Me CH CH CH N i-Pr Me CF₃ F CH CH CH N t-Bu Me CF₃ F CHCH CH N i-Pr Cl CF₃ F CH CH CH N t-Bu Cl CF₃ F CH CH CH N i-Pr Br CF₃ FCH CH CH N t-Bu Br CF₃ F CH CH CH N i-Pr Me Cl F CH CH CH N t-Bu Me Cl FCH CH CH N i-Pr Cl Cl F CH CH CH N t-Bu Cl Cl F CH CH CH N i-Pr Br Cl FCH CH CH N t-Bu Br Cl F CH CH CH N i-Pr Me Br F CH CH CH N t-Bu Me Br FCH CH CH N i-Pr Cl Br F CH CH CH N t-Bu Cl Br F CH CH CH N i-Pr Br Br FCH CH CH N t-Bu Br Br F CH CH CH N i-Pr Me CN F CH CH CH N t-Bu Me CN FCH CH CH N i-Pr Cl CN F CH CH CH N t-Bu Cl CN F CH CH CH N i-Pr Br CN FCH CH CH N t-Bu Br CN F CH CH CH N i-Pr Me CF₃ Cl CH CH CH N t-Bu Me CF₃Cl CH CH CH N i-Pr Cl CF₃ Cl CH CH CH N t-Bu Cl CF₃ Cl CH CH CH N i-PrBr CF₃ Cl CH CH CH N t-Bu Br CF₃ Cl CH CH CH N i-Pr Me Cl Cl CH CH CH Nt-Bu Me Cl Cl CH CH CH N i-Pr Cl Cl Cl CH CH CH N t-Bu Cl Cl Cl CH CH CHN i-Pr Br Cl Cl CH CH CH N t-Bu Br Cl Cl CH CH CH N i-Pr Me Br Cl CH CHCH N t-Bu Me Br Cl CH CH CH N i-Pr Cl Br Cl CH CH CH N t-Bu Cl Br Cl CHCH CH N i-Pr Br Br Cl CH CH CH N t-Bu Br Br Cl CH CH CH N i-Pr Me CN ClCH CH CH N t-Bu Me CN Cl CH CH CH N i-Pr Cl CN Cl CH CH CH N t-Bu Cl CNCl CH CH CH N i-Pr Br CN Cl CH CH CH N t-Bu Br CN Cl CH CH CH N i-Pr MeCF₃ Br CH CH CH N t-Bu Me CF₃ Br CH CH CH N i-Pr Cl CF₃ Br CH CH CH Nt-Bu Cl CF₃ Br CH CH CH N i-Pr Br CF₃ Br CH CH CH N t-Bu Br CF₃ Br CH CHCH N i-Pr Me Cl Br CH CH CH N t-Bu Me Cl Br CH CH CH N i-Pr Cl Cl Br CHCH CH N t-Bu Cl Cl Br CH CH CH N i-Pr Br Cl Br CH CH CH N t-Bu Br Cl BrCH CH CH N i-Pr Me Br Br CH CH CH N t-Bu Me Br Br CH CH CH N i-Pr Cl BrBr CH CH CH N t-Bu Cl Br Br CH CH CH N i-Pr Br Br Br CH CH CH N t-Bu BrBr Br CH CH CH N i-Pr Me CN Br CH CH CH N t-Bu Me CN Br CH CH CH N i-PrCl CN Br CH CH CH N t-Bu Cl CN Br CH CH CH N i-Pr Br CN Br CH CH CH Nt-Bu Br CN Br CH CH CH N i-Pr Me CF₃ CN CH CH CH N t-Bu Me CF₃ CN CH CHCH N i-Pr Cl CF₃ CN CH CH CH N t-Bu Cl CF₃ CN CH CH CH N i-Pr Br CF₃ CNCH CH CH N t-Bu Br CF₃ CN CH CH CH N i-Pr Me Cl CN CH CH CH N t-Bu Me ClCN CH CH CH N i-Pr Cl Cl CN CH CH CH N t-Bu Cl Cl CN CH CH CH N i-Pr BrCl CN CH CH CH N t-Bu Br Cl CN CH CH CH N i-Pr Me Br CN CH CH CH N t-BuMe Br CN CH CH CH N i-Pr Cl Br CN CH CH CH N t-Bu Cl Br CN CH CH CH Ni-Pr Br Br CN CH CH CH N t-Bu Br Br CN CH CH CH N i-Pr Me CN CN CH CH CHN t-Bu Me CN CN CH CH CH N i-Pr Cl CN CN CH CH CH N t-Bu Cl CN CN CH CHCH N i-Pr Br CN CN CH CH CH N t-Bu Br CN CN CH CH CH CH Me Me CF₃ F CHCH CH CH Et Me CF₃ F CH CH CH CH CH(CH₃)CH₂OCH₃ Me CF₃ F CH CH CH CHCH(CH₃)CH₂SCH₃ Me CF₃ F CH CH CH CH propargyl Me CF₃ F CH CH CH CH Me MeCF₃ Cl CH CH CH CH Et Me CF₃ Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Me CF₃ Cl CHCH CH CH CH(CH₃)CH₂SCH₃ Me CF₃ Cl CH CH CH CH propargyl Me CF₃ Cl CH CHCH CH Me Me Br F CH CH CH CH Et Me Br F CH CH CH CH CH(CH₃)CH₂OCH₃ Me BrF CH CH CH CH CH(CH₃)CH₂SCH₃ Me Br F CH CH CH CH propargyl Me Br F CH CHCH CH Me Me Br Cl CH CH CH CH Et Me Br Cl CH CH CH CH CH(CH₃)CH₂OCH₃ MeBr Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Me Br Cl CH CH CH CH propargyl Me Br ClCH CH CH CH Me Cl CF₃ F CH CH CH CH Et Cl CF₃ F CH CH CH CHCH(CH₃)CH₂OCH₃ Cl CF₃ F CH CH CH CH CH(CH₃)CH₂SCH₃ Cl CF₃ F CH CH CH CHpropargyl Cl CF₃ F CH CH CH CH Me Cl CF₃ Cl CH CH CH CH Et Cl CF₃ Cl CHCH CH CH CH(CH₃)CH₂OCH₃ Cl CF₃ Cl CH CH CH CH CH(CH₃)CH₂SCH₃ Cl CF₃ ClCH CH CH CH propargyl Cl CF₃ Cl CH CH CH CH Me Cl Br F CH CH CH CH Et ClBr F CH CH CH CH CH(CH₃)CH₂OCH₃ Cl Br F CH CH CH CH CH(CH₃)CH₂SCH₃ Cl BrF CH CH CH CH propargyl Cl Br F CH CH CH CH Me Cl Br Cl CH CH CH CH EtCl Br Cl CH CH CH CH CH(CH₃)CH₂OCH₃ Cl Br Cl CH CH CH CH CH(CH₃)CH₂SCH₃Cl Br Cl CH CH CH CH propargyl Cl Br Cl CH CH CH N Me Me CF₃ F CH CH CHN Et Me CF₃ F CH CH CH N CH(CH₃)CH₂OCH₃ Me CF₃ F CH CH CH NCH(CH₃)CH₂SCH₃ Me CF₃ F CH CH CH N propargyl Me CF₃ F CH CH CH N Me MeCF₃ Cl CH CH CH N Et Me CF₃ Cl CH CH CH N CH(CH₃)CH₂OCH₃ Me CF₃ Cl CH CHCH N CH(CH₃)CH₂SCH₃ Me CF₃ Cl CH CH CH N propargyl Me CF₃ Cl CH CH CH NMe Me Br F CH CH CH N Et Me Br F CH CH CH N CH(CH₃)CH₂OCH₃ Me Br F CH CHCH N CH(CH₃)CH₂SCH₃ Me Br F CH CH CH N propargyl Me Br F CH CH CH N MeMe Br Cl CH CH CH N Et Me Br Cl CH CH CH N CH(CH₃)CH₂OCH₃ Me Br Cl CH CHCH N CH(CH₃)CH₂SCH₃ Me Br Cl CH CH CH N propargyl Me Br Cl CH CH CH N MeCl CF₃ F CH CH CH N Et Cl CF₃ F CH CH CH N CH(CH₃)CH₂OCH₃ Cl CF₃ F CH CHCH N CH(CH₃)CH₂SCH₃ Cl CF₃ F CH CH CH N propargyl Cl CF₃ F CH CH CH N MeCl CF₃ Cl CH CH CH N Et Cl CF₃ Cl CH CH CH N CH(CH₃)CH₂OCH₃ Cl CF₃ Cl CHCH CH N CH(CH₃)CH₂SCH₃ Cl CF₃ Cl CH CH CH N propargyl Cl CF₃ Cl CH CH CHN Me Cl Br F CH CH CH N Et Cl Br F CH CH CH N CH(CH₃)CH₂OCH₃ Cl Br F CHCH CH N CH(CH₃)CH₂SCH₃ Cl Br F CH CH CH N propargyl Cl Br F CH CH CH NMe Cl Br Cl CH CH CH N Et Cl Br Cl CH CH CH N CH(CH₃)CH₂OCH₃ Cl Br Cl CHCH CH N CH(CH₃)CH₂SCH₃ Cl Br Cl CH CH CH N propargyl Cl Br Cl C—Cl CH CHCH i-Pr Me CF₃ Cl C—F CH CH CH i-Pr Me CF₃ F CH CH CH CH i-Pr Me CF₃C≡CH CH CH CH CH i-Pr Me CF₃ I CH CH CH CH i-Pr Me CF₃ SO₂Me C—Cl CH CHCH i-Pr Cl CF₃ Cl C—F CH CH CH i-Pr Cl CF₃ F CH CH CH CH i-Pr Cl CF₃C≡CH CH CH CH CH i-Pr Cl CF₃ I CH CH CH CH i-Pr Cl CF₃ SO₂Me C—Cl CH CHCH i-Pr Me Br Cl C—F CH CH CH i-Pr Me Br F CH CH CH CH i-Pr Me Br C≡CHCH CH CH CH i-Pr Me Br I CH CH CH CH i-Pr Me Br SO₂Me C—Cl CH CH CH i-PrCl Br Cl C—F CH CH CH i-Pr Cl Br F CH CH CH CH i-Pr Cl Br C≡CH CH CH CHCH i-Pr Cl Br I CH CH CH CH i-Pr Cl Br SO₂Me C—Cl CH CH N i-Pr Me CF₃ ClC—F CH CH N i-Pr Me CF₃ F CH CH CH N i-Pr Me CF₃ C≡CH CH CH CH N i-Pr MeCF₃ I CH CH CH N i-Pr Me CF₃ SO₂Me C—Cl CH CH N i-Pr Cl CF₃ Cl C—F CH CHN i-Pr Cl CF₃ F CH CH CH N i-Pr Cl CF₃ C≡CH CH CH CH N i-Pr Cl CF₃ I CHCH CH N i-Pr Cl CF₃ SO₂Me C—Cl CH CH N i-Pr Me Br Cl C—F CH CH N i-Pr MeBr F CH CH CH N i-Pr Me Br C≡CH CH CH CH N i-Pr Me Br I CH CH CH N i-PrMe Br SO₂Me C—Cl CH CH N i-Pr Cl Br Cl C—F CH CH N i-Pr Cl Br F CH CH CHN i-Pr Cl Br C≡CH CH CH CH N i-Pr Cl Br I CH CH CH N i-Pr Cl Br SO₂Me CHN CH N i-Pr Me CF₃ H CH N CH N i-Pr Me CF₃ Me CH N CH N i-Pr Me CF₃ ClCH N CH N i-Pr Cl CF₃ H CH N CH N i-Pr Cl CF₃ Me CH N CH N i-Pr Cl CF₃Cl CH N CH N i-Pr Me CN H CH N CH N i-Pr Me CN Me CH N CH N i-Pr Me CNCl CH N CH N i-Pr Cl CN H CH N CH N i-Pr Cl CN Me CH N CH N i-Pr Cl CNCl CH N CH N i-Pr Me Br H CH N CH N i-Pr Me Br Me CH N CH N i-Pr Me BrCl CH N CH N i-Pr Cl Br H CH N CH N i-Pr Cl Br Me CH N CH N i-Pr Cl BrCl CH N CH N t-Bu Me CF₃ H CH N CH N t-Bu Me CF₃ Me CH N CH N t-Bu MeCF₃ Cl CH N CH N t-Bu Cl CF₃ H CH N CH N t-Bu Cl CF₃ Me CH N CH N t-BuCl CF₃ Cl CH N CH N t-Bu Me CN H CH N CH N t-Bu Me CN Me CH N CH N t-BuMe CN Cl CH N CH N t-Bu Cl CN H CH N CH N t-Bu Cl CN Me CH N CH N t-BuCl CN Cl CH N CH N t-Bu Me Br H CH N CH N t-Bu Me Br Me CH N CH N t-BuMe Br Cl CH N CH N t-Bu Cl Br H CH N CH N t-Bu Cl Br Me CH N CH N t-BuCl Br Cl CH CH N N i-Pr Me CF₃ H CH CH N N i-Pr Me CF₃ Me CH CH N N i-PrMe CF₃ Cl CH CH N N i-Pr Cl CF₃ H CH CH N N i-Pr Cl CF₃ Me CH CH N Ni-Pr Cl CF₃ Cl CH CH N N i-Pr Me CN H CH CH N N i-Pr Me CN Me CH CH N Ni-Pr Me CN Cl CH CH N N i-Pr Cl CN H CH CH N N i-Pr Cl CN Me CH CH N Ni-Pr Cl CN Cl CH CH N N i-Pr Me Br H CH CH N N i-Pr Me Br Me CH CH N Ni-Pr Me Br Cl CH CH N N i-Pr Cl Br H CH CH N N i-Pr Cl Br Me CH CH N Ni-Pr Cl Br Cl CH CH N N i-Pr Me CF₃ H CH CH N N i-Pr Me CF₃ Me CH CH N Ni-Pr Me CF₃ Cl CH CH N N i-Pr Cl CF₃ H CH CH N N i-Pr Cl CF₃ Me CH CH NN i-Pr Cl CF₃ Cl CH CH N N i-Pr Me CN H CH CH N N i-Pr Me CN Me CH CH NN i-Pr Me CN Cl CH CH N N i-Pr Cl CN H CH CH N N i-Pr Cl CN Me CH CH N Ni-Pr Cl CN Cl CH CH N N i-Pr Me Br H CH CH N N i-Pr Me Br Me CH CH N Ni-Pr Me Br Cl CH CH N N i-Pr Cl Br H CH CH N N i-Pr Cl Br Me CH CH N Ni-Pr Cl Br Cl

[0241] TABLE 3

R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) Me CF₃ i-PrMe H H Me CF₃ t-Bu Me H H Me CF₃ i-Pr Me H Me Me CF₃ t-Bu Me H Me Me CF₃i-Pr Me Cl H Me CF₃ t-Bu Me Cl H Me CF₃ i-Pr Me Cl Me Me CF₃ t-Bu Me ClMe Me CF₃ i-Pr Me Me Me Me CF₃ t-Bu Me Me Me Cl CF₃ i-Pr Me H H Cl CF₃t-Bu Me H H Cl CF₃ i-Pr Me H Me Cl CF₃ t-Bu Me H Me Cl CF₃ i-Pr Me Cl HCl CF₃ t-Bu Me Cl H Cl CF₃ i-Pr Me Cl Me Cl CF₃ t-Bu Me Cl Me Cl CF₃i-Pr Me Me Me Cl CF₃ t-Bu Me Me Me

[0242] TABLE 4

R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) R⁴ R⁶ R³ R^(9a) R^(9b) R^(9c) Me CF₃ i-PrMe H Me Me CF₃ t-Bu Me H Me Me CF₃ i-Pr Me Me Me Me CF₃ t-Bu Me Me Me MeCF₃ i-Pr Cl H Me Me CF₃ t-Bu Cl H Me Me CF₃ i-Pr Cl Me Me Me CF₃ t-Bu ClMe Me Cl CF₃ i-Pr Me H Me Cl CF₃ t-Bu Me H Me Cl CF₃ i-Pr Mc Me Me ClCF₃ t-Bu Me Me Me Cl CF₃ i-Pr Cl H Me Cl CF₃ t-Bu Cl H Me Cl CF₃ i-Pr ClMe Me Cl CF₃ t-Bu Cl Me Me

[0243] TABLE 5

R⁴ R⁵ R⁶ R³ R⁹ R⁴ R⁵ R⁶ R³ R⁹ CH₃ F CF₃ Me Cl Cl Br Cl Me Br CH₃ F CF₃Et Cl Cl Br Cl Et Br CH₃ F CF₃ i-Pr Cl Cl Br Cl i-Pr Br CH₃ F CF₃ t-BuCl Cl Br Cl i-Bu Br CH₃ F CF₃ Me Br Cl Br Br Me Cl CH₃ F CF₃ Et Br Cl BrBr Et Cl CH₃ F CF₃ i-Pr Br Cl Br Br i-Pr Cl CH₃ F CF₃ t-Bu Br Cl Br Brt-Bu Cl CH₃ F Cl Me Cl Cl Br Br Me Br CH₃ F Cl Et Cl Cl Br Br Et Br CH₃F Cl i-Pr Cl Cl Br Br i-Pr Br CH₃ F Cl t-Bu Cl Cl Br Br t-Bu Br CH₃ F ClMe Br Cl I CF₃ Me Cl CH₃ F Cl Et Br Cl I CF₃ Et Cl CH₃ F Cl i-Pr Br Cl ICF₃ i-Pr Cl CH₃ F Cl t-Bu Br Cl I CF₃ t-Bu Cl CH₃ F Br Me Cl Cl I CF₃ MeBr CH₃ F Br Et Cl Cl I CF₃ Et Br CH₃ F Br i-Pr Cl Cl I CF₃ i-Pr Br CH₃ FBr t-Bu Cl Cl I CF₃ t-Bu Br CH₃ F Br Me Br Cl I Cl Me Cl CH₃ F Br Et BrCl I Cl Et Cl CH₃ F Br i-Pr Br Cl I Cl i-Pr Cl CH₃ F Br t-Bu Br Cl I Clt-Bu Cl CH₃ Cl CF₃ Me Cl Cl I Cl Me Br CH₃ Cl CF₃ Et Cl Cl I Cl Et BrCH₃ Cl CF₃ i-Pr Cl Cl I Cl i-Pr Br CH₃ Cl CF₃ t-Bu Cl Cl I Cl t-Bu BrCH₃ Cl CF₃ Me Br Cl I Br Me Cl CH₃ Cl CF₃ Et Br Cl I Br Et Cl CH₃ Cl CF₃i-Pr Br Cl I Br i-Pr Cl CH₃ Cl CF₃ t-Bu Br Cl I Br t-Bu Cl CH₃ Cl Cl MeCl Cl I Br Me Br CH₃ Cl Cl Et Cl Cl I Br Et Br CH₃ Cl Cl i-Pr Cl Cl I Bri-Pr Br CH₃ Cl Cl t-Bu Cl Cl I Br t-Bu Br CH₃ Cl Cl Me Br Cl CF₃ CF₃ MeCl CH₃ Cl Cl Et Br Cl CF₃ CF₃ Et Cl CH₃ Cl Cl i-Pr Br Cl CF₃ CF₃ i-Pr ClCH₃ Cl Cl t-Bu Br Cl CF₃ CF₃ t-Bu Cl CH₃ Cl Br Me Cl Cl CF₃ CF₃ Me BrCH₃ Cl Br Et Cl Cl CF₃ CF₃ Et Br CH₃ Cl Br i-Pr Cl Cl CF₃ CF₃ i-Pr BrCH₃ Cl Br t-Bu Cl Cl CF₃ CF₃ t-Bu Br CH₃ Cl Br Me Br Cl CF₃ Cl Me Cl CH₃Cl Br Et Br Cl CF₃ Cl Et Cl CH₃ Cl Br i-Pr Br Cl CF₃ Cl i-Pr Cl CH₃ ClBr t-Bu Br Cl CF₃ Cl t-Bu Cl CH₃ Br CF₃ Me Cl Cl CF₃ Cl Me Br CH₃ Br CF₃Et Cl Cl CF₃ Cl Et Br CH₃ Br CF₃ i-Pr Cl Cl CF₃ Cl i-Pr Br CH₃ Br CF₃t-Bu Cl Cl CF₃ Cl t-Bu Br CH₃ Br CF₃ Me Br Cl CF₃ Br Me Cl CH₃ Br CF₃ EtBr Cl CF₃ Br Et Cl CH₃ Br CF₃ i-Pr Br Cl CF₃ Br i-Pr Cl CH₃ Br CF₃ t-BuBr Cl CF₃ Br t-Bu Cl CH₃ Br Cl Me Cl Cl CF₃ Br Me Br CH₃ Br Cl Et Cl ClCF₃ Br Et Br CH₃ Br Cl i-Pr Cl Cl CF₃ Br i-Pr Br CH₃ Br Cl t-Bu Cl ClCF₃ Br t-Bu Br CH₃ Br Cl Me Br Cl Cl Cl n-Pr Cl CH₃ Br Cl Et Br Cl Cl Cln-Bu Cl CH₃ Br Cl i-Pr Br Cl Cl Cl s-Bu Cl CH₃ Br Cl t-Bu Br Cl Cl Cli-Bu Cl CH₃ Br Br Me Cl Br F CF₃ Me Cl CH₃ Br Br Et Cl Br F CF₃ Et ClCH₃ Br Br i-Pr Cl Br F CF₃ i-Pr Cl CH₃ Br Br t-Bu Cl Br F CF₃ t-Bu ClCH₃ Br Br Me Br Br F CF₃ Me Br CH₃ Br Br Et Br Br F CF₃ Et Br CH₃ Br Bri-Pr Br Br F CF₃ i-Pr Br CH₃ Br Br t-Bu Br Br F CF₃ t-Bu Br CH₃ I CF₃ MeCl Br F Cl Me Cl CH₃ I CF₃ Et Cl Br F Cl Et Cl CH₃ I CF₃ i-Pr Cl Br F Cli-Pr Cl CH₃ I CF₃ t-Bu Cl Br F Cl t-Bu Cl CH₃ I CF₃ Me Br Br F Cl Me BrCH₃ I CF₃ Et Br Br F Cl Et Br CH₃ I CF₃ i-Pr Br Br F Cl i-Pr Br CH₃ ICF₃ t-Bu Br Br F Cl t-Bu Br CH₃ I Cl Me Cl Br F Br Me Cl CH₃ I Cl Et ClBr F Br Et Cl CH₃ I Cl i-Pr Cl Br F Br i-Pr Cl CH₃ I Cl t-Bu Cl Br F Brt-Bu Cl CH₃ I Cl Me Br Br F Br Me Br CH₃ I Cl Et Br Br F Br Et Br CH₃ ICl i-Pr Br Br F Br i-Pr Br CH₃ I Cl t-Bu Br Br F Br t-Bu Br CH₃ I Br MeCl Br Cl CF₃ Me Cl CH₃ I Br Et Cl Br Cl CF₃ Et Cl CH₃ I Br i-Pr Cl Br ClCF₃ i-Pr Cl CH₃ I Br t-Bu Cl Br Cl CF₃ t-Bu Cl CH₃ I Br Me Br Br Cl CF₃Me Br CH₃ I Br Et Br Br Cl CF₃ Et Br CH₃ I Br i-Pr Br Br Cl CF₃ i-Pr BrCH₃ I Br t-Bu Br Br Cl CF₃ t-Bu Br CH₃ CF₃ CF₃ Me Cl Br Cl Cl Me Cl CH₃CF₃ CF₃ Et Cl Br Cl Cl Et Cl CH₃ CF₃ CF₃ i-Pr Cl Br Cl Cl i-Pr Cl CH₃CF₃ CF₃ t-Bu Cl Br Cl Cl t-Bu Cl CH₃ CF₃ CF₃ Me Br Br Cl Cl Me Br CH₃CF₃ CF₃ Et Br Br Cl Cl Et Br CH₃ CF₃ CF₃ i-Pr Br Br Cl Cl i-Pr Br CH₃CF₃ CF₃ t-Bu Br Br Cl Cl t-Bu Br CH₃ CF₃ Cl Me Cl Br Cl Br Me Cl CH₃ CF₃Cl Et Cl Br Cl Br Et Cl CH₃ CF₃ Cl i-Pr Cl Br Cl Br i-Pr Cl CH₃ CF₃ Clt-Bu Cl Br Cl Br t-Bu Cl CH₃ CF₃ Cl Me Br Br Cl Br Me Br CH₃ CF₃ Cl EtBr Br Cl Br Et Br CH₃ CF₃ Cl i-Pr Br Br Cl Br i-Pr Br CH₃ CF₃ Cl t-Bu BrBr Cl Br t-Bu Br CH₃ CF₃ Br Me Cl Br Br CF₃ Me Cl CH₃ CF₃ Br Et Cl Br BrCF₃ Et Cl CH₃ CF₃ Br i-Pr Cl Br Br CF₃ i-Pr Cl CH₃ CF₃ Br t-Bu Cl Br BrCF₃ t-Bu Cl CH₃ CF₃ Br Me Br Br Br CF₃ Me Br CH₃ CF₃ Br Et Br Br Br CF₃Et Br CH₃ CF₃ Br i-Pr Br Br Br CF₃ i-Pr Br CH₃ CF₃ Br t-Bu Br Br Br CF₃t-Bu Br CH₃ Cl Cl n-Pr Cl Br Br Cl Me Cl CH₃ Cl Cl n-Bu Cl Br Br Cl EtCl CH₃ Cl Cl s-Bu Cl Br Br Cl i-Pr Cl CH₃ Cl Cl i-Bu Cl Br Br Cl t-Bu ClCl F CF₃ Me Cl Br Br Cl Me Br Cl F CF₃ Et Cl Br Br Cl Et Br Cl F CF₃i-Pr Cl Br Br Cl i-Pr Br Cl F CF₃ t-Bu Cl Br Br Cl t-Bu Br Cl F CF₃ MeBr Br Br Br Me Cl Cl F CF₃ Et Br Br Br Br Et Cl Cl F CF₃ i-Pr Br Br BrBr i-Pr Cl Cl F CF₃ t-Bu Br Br Br Br t-Bu Cl Cl F Cl Me Cl Br Br Br MeBr Cl F Cl Et Cl Br Br Br Et Br Cl F Cl i-Pr Cl Br Br Br i-Pr Br Cl F Clt-Bu Cl Br Br Br t-Bu Br Cl F Cl Me Br Br I CF₃ Me Cl Cl F Cl Et Br Br ICF₃ Et Cl Cl F Cl i-Pr Br Br I CF₃ i-Pr Cl Cl F Cl t-Bu Br Br I CF₃ t-BuCl Cl F Br Me Cl Br I CF₃ Me Br Cl F Br Et Cl Br I CF₃ Et Br Cl F Bri-Pr Cl Br I CF₃ i-Pr Br Cl F Br t-Bu Cl Br I CF₃ t-Bu Br Cl F Br Me BrBr I Cl Me Cl Cl F Br Et Br Br I Cl Et Cl Cl F Br i-Pr Br Br I Cl i-PrCl Cl F Br t-Bu Br Br I Cl t-Bu Cl Cl Cl CF₃ Me Cl Br I Cl Me Br Cl ClCF₃ Et Cl Br I Cl Et Br Cl Cl CF₃ i-Pr Cl Br I Cl i-Pr Br Cl Cl CF₃ t-BuCl Br I Cl t-Bu Br Cl Cl CF₃ Me Br Br I Br Me Cl Cl Cl CF₃ Et Br Br I BrEt Cl Cl Cl CF₃ i-Pr Br Br I Br i-Pr Cl Cl Cl CF₃ t-Bu Br Br I Br t-BuCl Cl Cl Cl Me Cl Br I Br Me Br Cl Cl Cl Et Cl Br I Br Et Br Cl Cl Cli-Pr Cl Br I Br i-Pr Br Cl Cl Cl t-Bu Cl Br I Br t-Bu Br Cl Cl Cl Me BrBr CF₃ CF₃ Me Cl Cl Cl Cl Et Br Br CF₃ CF₃ Et Cl Cl Cl Cl i-Pr Br Br CF₃CF₃ i-Pr Cl Cl Cl Cl t-Bu Br Br CF₃ CF₃ t-Bu Cl Cl Cl Br Me Cl Br CF₃CF₃ Me Br Cl Cl Br Et Cl Br CF₃ CF₃ Et Br Cl Cl Br i-Pr Cl Br CF₃ CF₃i-Pr Br Cl Cl Br t-Bu Cl Br CF₃ CF₃ t-Bu Br Cl Cl Br Me Br Br CF₃ Cl MeCl Cl Cl Br Et Br Br CF₃ Cl Et Cl Cl Cl Br i-Pr Br Br CF₃ Cl i-Pr Cl ClCl Br t-Bu Br Br CF₃ Cl t-Bu Cl Cl Br CF₃ Me Cl Br CF₃ Cl Me Br Cl BrCF₃ Et Cl Br CF₃ Cl Et Br Cl Br CF₃ i-Pr Cl Br CF₃ Cl i-Pr Br Cl Br CF₃t-Bu Cl Br CF₃ Cl t-Bu Br Cl Br CF₃ Me Br Br CF₃ Br Me Cl Cl Br CF₃ EtBr Br CF₃ Br Et Cl Cl Br CF₃ i-Pr Br Br CF₃ Br i-Pr Cl Cl Br CF₃ t-Bu BrBr CF₃ Br t-Bu Cl Cl Br Cl Me Cl Br CF₃ Br Me Br Cl Br Cl Et Cl Br CF₃Br Et Br Cl Br Cl i-Pr Cl Br CF₃ Br i-Pr Br Cl Br Cl t-Bu Cl Br CF₃ Brt-Bu Br

[0244] TABLE 6

R⁴ R⁵ R⁶ R³ R⁹ R⁴ R⁵ R⁶ R³ R⁹ CH₃ F CF₃ Me Cl Cl Br Cl Me Br CH₃ F CF₃Et Cl Cl Br Cl Et Br CH₃ F CF₃ i-Pr Cl Cl Br Cl i-Pr Br CH₃ F CF₃ t-BuCl Cl Br Cl t-Bu Br CH₃ F CF₃ Me Br Cl Br Br Me Cl CH₃ F CF₃ Et Br Cl BrBr Et Cl CH₃ F CF₃ i-Pr Br Cl Br Br i-Pr Cl CH₃ F CF₃ t-Bu Br Cl Br Brt-Bu Cl CH₃ F Cl Me Cl Cl Br Br Me Br CH₃ F Cl Et Cl Cl Br Br Et Br CH₃F Cl i-Pr Cl Cl Br Br i-Pr Br CH₃ F Cl t-Bu Cl Cl Br Br t-Bu Br CH₃ F ClMe Br Cl I CF₃ Me Cl CH₃ F Cl Et Br Cl I CF₃ Et Cl CH₃ F Cl i-Pr Br Cl ICF₃ i-Pr Cl CH₃ F Cl t-Bu Br Cl I CF₃ t-Bu Cl CH₃ F Br Me Cl Cl I CF₃ MeBr CH₃ F Br Et Cl Cl I CF₃ Et Br CH₃ F Br i-Pr Cl Cl I CF₃ i-Pr Br CH₃ FBr t-Bu Cl Cl I CF₃ t-Bu Br CH₃ F Br Me Br Cl I Cl Me Cl CH₃ F Br Et BrCl I Cl Et Cl CH₃ F Br i-Pr Br Cl I Cl i-Pr Cl CH₃ F Br t-Bu Br Cl I Clt-Bu Cl CH₃ Cl CF₃ Me Cl Cl I Cl Me Br CH₃ Cl CF₃ Et Cl Cl I Cl Et BrCH₃ Cl CF₃ i-Pr Cl Cl I Cl i-Pr Br CH₃ Cl CF₃ t-Bu Cl Cl I Cl t-Bu BrCH₃ Cl CF₃ Me Br Cl I Br Me Cl CH₃ Cl CF₃ Et Br Cl I Br Et Cl CH₃ Cl CF₃i-Pr Br Cl I Br i-Pr Cl CH₃ Cl CF₃ t-Bu Br Cl I Br t-Bu Cl CH₃ Cl Cl MeCl Cl I Br Me Br CH₃ Cl Cl Et Cl Cl I Br Et Br CH₃ Cl Cl i-Pr Cl Cl I Bri-Pr Br CH₃ Cl Cl t-Bu Cl Cl I Br t-Bu Br CH₃ Cl Cl Me Br Cl CF₃ CF₃ MeCl CH₃ Cl Cl Et Br Cl CF₃ CF₃ Et Cl CH₃ Cl Cl i-Pr Br Cl CF₃ CF₃ i-Pr ClCH₃ Cl Cl t-Bu Br Cl CF₃ CF₃ t-Bu Cl CH₃ Cl Br Me Cl Cl CF₃ CF₃ Me BrCH₃ Cl Br Et Cl Cl CF₃ CF₃ Et Br CH₃ Cl Br i-Pr Cl Cl CF₃ CF₃ i-Pr BrCH₃ Cl Br t-Bu Cl Cl CF₃ CF₃ t-Bu Br CH₃ Cl Br Me Br Cl CF₃ Cl Me Cl CH₃Cl Br Et Br Cl CF₃ Cl Et Cl CH₃ Cl Br i-Pr Br Cl CF₃ Cl i-Pr Cl CH₃ ClBr t-Bu Br Cl CF₃ Cl t-Bu Cl CH₃ Br CF₃ Me Cl Cl CF₃ Cl Me Br CH₃ Br CF₃Et Cl Cl CF₃ Cl Et Br CH₃ Br CF₃ i-Pr Cl Cl CF₃ Cl i-Pr Br CH₃ Br CF₃t-Bu Cl Cl CF₃ Cl t-Bu Br CH₃ Br CF₃ Me Br Cl CF₃ Br Me Cl CH₃ Br CF₃ EtBr Cl CF₃ Br Et Cl CH₃ Br CF₃ i-Pr Br Cl CF₃ Br i-Pr Cl CH₃ Br CF₃ t-BuBr Cl CF₃ Br t-Bu Cl CH₃ Br Cl Me Cl Cl CF₃ Br Me Br CH₃ Br Cl Et Cl ClCF₃ Br Et Br CH₃ Br Cl i-Pr Cl Cl CF₃ Br i-Pr Br CH₃ Br Cl t-Bu Cl ClCF₃ Br t-Bu Br CH₃ Br Cl Me Br Cl Cl Cl n-Pr Cl CH₃ Br Cl Et Br Cl Cl Cln-Bu Cl CH₃ Br Cl i-Pr Br Cl Cl Cl s-Bu Cl CH₃ Br Cl t-Bu Br Cl Cl Cli-Bu Cl CH₃ Br Br Me Cl Br F CF₃ Me Cl CH₃ Br Br Et Cl Br F CF₃ Et ClCH₃ Br Br i-Pr Cl Br F CF₃ i-Pr Cl CH₃ Br Br t-Bu Cl Br F CF₃ t-Bu ClCH₃ Br Br Me Br Br F CF₃ Me Br CH₃ Br Br Et Br Br F CF₃ Et Br CH₃ Br Bri-Pr Br Br F CF₃ i-Pr Br CH₃ Br Br t-Bu Br Br F CF₃ t-Bu Br CH₃ I CF₃ MeCl Br F Cl Me Cl CH₃ I CF₃ Et Cl Br F Cl Et Cl CH₃ I CF₃ i-Pr Cl Br F Cli-Pr Cl CH₃ I CF₃ t-Bu Cl Br F Cl t-Bu Cl CH₃ I CF₃ Me Br Br F Cl Me BrCH₃ I CF₃ Et Br Br F Cl Et Br CH₃ I CF₃ i-Pr Br Br F Cl i-Pr Br CH₃ ICF₃ t-Bu Br Br F Cl t-Bu Br CH₃ I Cl Me Cl Br F Br Me Cl CH₃ I Cl Et ClBr F Br Et Cl CH₃ I Cl i-Pr Cl Br F Br i-Pr Cl CH₃ I Cl t-Bu Cl Br F Brt-Bu Cl CH₃ I Cl Me Br Br F Br Me Br CH₃ I Cl Et Br Br F Br Et Br CH₃ ICl i-Pr Br Br F Br i-Pr Br CH₃ I Cl t-Bu Br Br F Br t-Bu Br CH₃ I Br MeCl Br Cl CF₃ Me Cl CH₃ I Br Et Cl Br Cl CF₃ Et Cl CH₃ I Br i-Pr Cl Br ClCF₃ i-Pr Cl CH₃ I Br t-Bu Cl Br Cl CF₃ t-Bu Cl CH₃ I Br Me Br Br Cl CF₃Me Br CH₃ I Br Et Br Br Cl CF₃ Et Br CH₃ I Br i-Pr Br Br Cl CF₃ i-Pr BrCH₃ I Br t-Bu Br Br Cl CF₃ t-Bu Br CH₃ CF₃ CF₃ Me Cl Br Cl Cl Me Cl CH₃CF₃ CF₃ Et Cl Br Cl Cl Et Cl CH₃ CF₃ CF₃ i-Pr Cl Br Cl Cl i-Pr Cl CH₃CF₃ CF₃ t-Bu Cl Br Cl Cl t-Bu Cl CH₃ CF₃ CF₃ Me Br Br Cl Cl Me Br CH₃CF₃ CF₃ Et Br Br Cl Cl Et Br CH₃ CF₃ CF₃ i-Pr Br Br Cl Cl i-Pr Br CH₃CF₃ CF₃ t-Bu Br Br Cl Cl t-Bu Br CH₃ CF₃ Cl Me Cl Br Cl Br Me Cl CH₃ CF₃Cl Et Cl Br Cl Br Et Cl CH₃ CF₃ Cl i-Pr Cl Br Cl Br i-Pr Cl CH₃ CF₃ Clt-Bu Cl Br Cl Br t-Bu Cl CH₃ CF₃ Cl Me Br Br Cl Br Me Br CH₃ CF₃ Cl EtBr Br Cl Br Et Br CH₃ CF₃ Cl i-Pr Br Br Cl Br i-Pr Br CH₃ CF₃ Cl t-Bu BrBr Cl Br t-Bu Br CH₃ CF₃ Br Me Cl Br Br CF₃ Me Cl CH₃ CF₃ Br Et Cl Br BrCF₃ Et Cl CH₃ CF₃ Br i-Pr Cl Br Br CF₃ i-Pr Cl CH₃ CF₃ Br t-Bu Cl Br BrCF₃ t-Bu Cl CH₃ CF₃ Br Me Br Br Br CF₃ Me Br CH₃ CF₃ Br Et Br Br Br CF₃Et Br CH₃ CF₃ Br i-Pr Br Br Br CF₃ i-Pr Br CH₃ CF₃ Br t-Bu Br Br Br CF₃t-Bu Br CH₃ Cl Cl n-Pr Cl Br Br Cl Me Cl CH₃ Cl Cl n-Bu Cl Br Br Cl EtCl CH₃ Cl Cl s-Bu Cl Br Br Cl i-Pr Cl CH₃ Cl Cl i-Bu Cl Br Br Cl t-Bu ClCl F CF₃ Me Cl Br Br Cl Me Br Cl F CF₃ Et Cl Br Br Cl Et Br Cl F CF₃i-Pr Cl Br Br Cl i-Pr Br Cl F CF₃ t-Bu Cl Br Br Cl t-Bu Br Cl F CF₃ MeBr Br Br Br Me Cl Cl F CF₃ Et Br Br Br Br Et Cl Cl F CF₃ i-Pr Br Br BrBr i-Pr Cl Cl F CF₃ t-Bu Br Br Br Br t-Bu Cl Cl F Cl Me Cl Br Br Br MeBr Cl F Cl Et Cl Br Br Br Et Br Cl F Cl i-Pr Cl Br Br Br i-Pr Br Cl F Clt-Bu Cl Br Br Br t-Bu Br Cl F Cl Me Br Br I CF₃ Me Cl Cl F Cl Et Br Br ICF₃ Et Cl Cl F Cl i-Pr Br Br I CF₃ i-Pr Cl Cl F Cl t-Bu Br Br I CF₃ t-BuCl Cl F Br Me Cl Br I CF₃ Me Br Cl F Br Et Cl Br I CF₃ Et Br Cl F Bri-Pr Cl Br I CF₃ i-Pr Br Cl F Br t-Bu Cl Br I CF₃ t-Bu Br Cl F Br Me BrBr I Cl Me Cl Cl F Br Et Br Br I Cl Et Cl Cl F Br i-Pr Br Br I Cl i-PrCl Cl F Br t-Bu Br Br I Cl t-Bu Cl Cl Cl CF₃ Me Cl Br I Cl Me Br Cl ClCF₃ Et Cl Br I Cl Et Br Cl Cl CF₃ i-Pr Cl Br I Cl i-Pr Br Cl Cl CF₃ t-BuCl Br I Cl t-Bu Br Cl Cl CF₃ Me Br Br I Br Me Cl Cl Cl CF₃ Et Br Br I BrEt Cl Cl Cl CF₃ i-Pr Br Br I Br i-Pr Cl Cl Cl CF₃ t-Bu Br Br I Br t-BuCl Cl Cl Cl Me Cl Br I Br Me Br Cl Cl Cl Et Cl Br I Br Et Br Cl Cl Cli-Pr Cl Br I Br i-Pr Br Cl Cl Cl t-Bu Cl Br I Br t-Bu Br Cl Cl Cl Me BrBr CF₃ CF₃ Me Cl Cl Cl Cl Et Br Br CF₃ CF₃ Et Cl Cl Cl Cl i-Pr Br Br CF₃CF₃ i-Pr Cl Cl Cl Cl t-Bu Br Br CF₃ CF₃ r-Bu Cl Cl Cl Br Me Cl Br CF₃CF₃ Me Br Cl Cl Br Et Cl Br CF₃ CF₃ Et Br Cl Cl Br i-Pr Cl Br CF₃ CF₃i-Pr Br Cl Cl Br t-Bu Cl Br CF₃ CF₃ t-Bu Br Cl Cl Br Me Br Br CF₃ Cl MeCl Cl Cl Br Et Br Br CF₃ Cl Et Cl Cl Cl Br i-Pr Br Br CF₃ Cl i-Pr Cl ClCl Br t-Bu Br Br CF₃ Cl t-Bu Cl Cl Br CF₃ Me Cl Br CF₃ Cl Me Br Cl BrCF₃ Et Cl Br CF₃ Cl Et Br Cl Br CF₃ i-Pr Cl Br CF₃ Cl i-Pr Br Cl Br CF₃t-Bu Cl Br CF₃ Cl t-Bu Br Cl Br CF₃ Me Br Br CF₃ Br Me Cl Cl Br CF₃ EtBr Br CF₃ Br Et Cl Cl Br CF₃ i-Pr Br Br CF₃ Br i-Pr Cl Cl Br CF₃ t-Bu BrBr CF₃ Br t-Bu Cl Cl Br Cl Me Cl Br CF₃ Br Me Br Cl Br Cl Et Cl Br CF₃Br Et Br Cl Br Cl i-Pr Cl Br CF₃ Br i-Pr Br Cl Br Cl t-Bu Cl Br CF₃ Brt-Bu Br

[0245] Formulation/Utility

[0246] Compounds of Formula I have been discovered to not only haveexcellent activity controlling phytophagous invertebrate pests, but alsohave favorable residual patterns and plant translocation to provideprotection of a plant developing from a plant propagule such as a seed,bulb, rhizome, tuber, corm, or stem or leaf cutting. (In the context ofthis disclosure “invertebrate pest control” means inhibition ofinvertebrate pest development (including mortality) that causessignificant reduction in feeding or other injury or damage caused by thepest; related expressions are defined analogously.) This invention thusprovides a method for protecting a plant propagule from phytophagousinvertebrate pests by contacting the propagule or the locus of thepropagule with a biologically effective amount of a compound of FormulaI. The method of this invention using a sufficient amount of the FormulaI compound has also been discovered to protect not only the propaguleitself but also new growth developing from the propagule.

[0247] As described herein, “treating” a propagule or locus of apropagule means applying a compound of Formula I or compositioncontaining the compound to the propagule or locus of the propagule sothat the compound of Formula I is brought in contact with the propagule;related terms such as “treatment” are defined analogously. When apropagule is thus brought into contact with a biologically effectiveamount of a Formula I compound, the compound protects it against injuryby phytophagous invertebrate pests. Not only does the Formula I compoundprotect the external surface of the propagule, but it will be absorbedby the propagule to produce a propagule comprising the Formula Icompound. If the propagule is contacted with sufficient amount ofFormula I compound, enough will be absorbed to produce a biologicallyeffective concentration of Formula I compound inside the propagule, andhence a propagule comprising a biologically effective amount of theFormula I compound. If a sufficient amount of the Formula I compound isapplied to raise the concentration of Formula I compound in thepropagule to a concentration greater than the minimum for biologicaleffectiveness then translocation can move a biologically effectiveconcentration of the Formula I compound to the developing shoot and rootto protect them as well.

[0248] As referred to in this disclosure, the term “invertebrate pest”includes arthropods, gastropods and nematodes of economic importance aspests. The term “phytophagous invertebrate pest” refers to invertebratepests causing injury to plants by feeding upon them, such as by eatingfoliage, stem, leaf, fruit or seed tissue or by sucking the vascularjuices of plants. The term “arthropod” includes insects, mites,centipedes, millipedes, pill bugs and symphylans. The term “gastropod”includes snails, slugs and other Stylommatophora. The term “nematode”includes the phytophagous nematodes (Phylum or Class Nematoda).Economically important phytophagous invertebrate pests include: larvaeof the order Lepidoptera, such as armyworms, cutworms, loopers, andheliothines in the family Noctuidae (e.g., fall armyworm (Spodopterafugiperda J. E. Smith), beet armyworm (Spodoptera exigua Hübner), blackcutworm (Agrotis ipsilon Hufnagel), cabbage looper (Trichoplusia niHübner), tobacco budworm (Heliothis virescens Fabricius)); borers,casebearers, webworms, coneworms, cabbageworms and skeletonizers fromthe family Pyralidae (e.g., European corn borer (Ostrinia nubilalisHübner), navel orangeworm (Amyelois transitella Walker), corn rootwebworm (Crambus caliginosellus Clemens), sod webworm (Herpetogrammalicarsisalis Walker)); leafrollers, budworms, seed worms, and fruitworms in the family Tortricidae (e.g., codling moth (Cydia pomonella L.(L. means Linnaeus)), grape berry moth (Endopiza viteana Clemens),oriental fruit moth (Grapholita molesta Busck)); and many othereconomically important lepidoptera (e.g., diamondback moth (Plutellaxylostella L.), pink bollworm (Pectinophora gossypiella Saunders), gypsymoth (Lymantria dispar L.)); foliar feeding larvae and adults of theorder Coleoptera including weevils from the families Anthribidae,Bruchidae, and Curculionidae (e.g., boll weevil (Anthonomus grandisBoheman), rice water weevil (Lissorhoptnrs oryzophilus Kuschel), riceweevil (Sitophilus oryzae L.)); flea beetles, cucumber beetles,rootworms, leaf beetles, potato beetles, and leafminers in the familyChrysomelidae (e.g., Colorado potato beetle (Leptinotarsa decemlineataSay), western corn rootworm (Diabrotica virgifera virgifera LeConte));chafers and other beetles from the family Scaribaeidae (e.g., Japanesebeetle (Popillia japonica Newman) and European chafer (Rhizotrogusmajalis Razoumowsky)); wireworms from the family Elateridae and barkbeetles from the family Scolytidae; adults and larvae of the orderDermaptera including earwigs from the family Forficulidae (e.g.,European earwig (Forficula auricularia L.), black earwig (Chelisochesmorio Fabricius)); adults and nymphs of the orders Hemiptera andHomoptera such as, plant bugs from the family Miridae, cicadas from thefamily Cicadidae, leafhoppers (e.g. Empoasca spp.) from the familyCicadellidae, planthoppers from the families Fulgoroidae andDelphacidae, treehoppers from the family Membracidae, psyllids from thefamily Psylidae, whiteflies from the family Aleyrodidae, aphids from thefamily Aphididae, phylloxera from the family Phylloxeridae, mealybugsfrom the family Pseudococcidae, scales from the families Coccidae,Diaspididae and Margarodidae, lace bugs from the family Tingidae, stinkbugs from the family Pentatomidae, cinch bugs (e.g., Blissus spp.) andother seed bugs from the family Lygaeidae, spittlebugs from the familyCercopidae squash bugs from the family Coreidae, and red bugs and cottonstainers from the family Pyrrhocoridae; adults and larvae of the orderAcari (mites) such as spider mites and red mites in the familyTetranychidae (e.g., European red mite (Panonychus ulmi Koch), twospotted spider mite (Tetranychus urticae Koch), McDaniel mite(Tetranychus mcdanieli McGregor)), flat mites in the familyTenuipalpidae (e.g., citrus flat mite (Brevipalpus lewisi McGregor)),rust and bud mites in the family Eriophyidae and other foliar feedingmites; adults and immatures of the order Orthoptera includinggrasshoppers, locusts and crickets (e.g., migratory grasshoppers (e.g.,Melanoplus sanguinipes Fabricius, M. differentialis Thomas), Americangrasshoppers (e.g., Schistocerca americana Drury), desert locust(Schistocerca gregaria Forskal), migratory locust (Locusta migratoriaL.), mole crickets (Gryllotalpa spp.)); adults and immatures of theorder Diptera including leafminers, midges, fruit flies (Tephritidae),frit flies (e.g., Oscinellafrit L.), soil maggots and other Nematocera;adults and immatures of the order Thysanoptera including onion thrips(Thrips tabaci Lindeman) and other fohar feeding thrips; and centipedesin the order Scutigeromorpha; and members of the Phylum or ClassNematoda including such important agricultural pests as root knotnematodes in the genus Meloidogyne, lesion nematodes in the genusPratylenchus, stubby root nematodes in the genus Trichodorus, etc.

[0249] Those skilled in the art will recognize that not all compoundsare equally effective against all pests. Compounds of the invention showparticularly high activity against pests in the order Lepidoptera (e.g.,Alabama argillacea Hübner (cotton leaf worm), Archips argyrospila Walker(fruit tree leaf roller), A. rosana L. (European leaf roller) and otherArchips species, Chilo suppressalis Walker (rice stem borer),Cnaphalocrosis medinalis Guenee (rice leaf roller), Crambuscaliginosellus Clemens (corn root webworm), Crambus teterrellus Zincken(bluegrass webworm), Cydia pomonella L. (codling moth), Earias insulanaBoisduval (spiny bollworm), Earias vittella Fabricius (spottedbollworm), Helicoverpa armigera Hübner (American bollworm), Helicoverpazea Boddie (corn earworm), Heliothis virescens Fabricius (tobaccobudworm), Herpetogramma licarsisalis Walker (sod webworm), Lobesiabotrana Denis & Schiffermuller (grape berry moth), Pectinophoragossypiella Saunders (pink bollworm), Phyllocnistis citrella Stainton(citrus leafminer), Pieris brassicae L. (large white butterfly), Pierisrapae L. (small white butterfly), Plutella xylostella L. (diamondbackmoth), Spodoptera exigua Hübner (beet armyworm), Spodoptera lituraFabricius (tobacco cutworm, cluster caterpillar), Spodoptera frugiperdaJ. E. Smith (fall armyworm), Trichoplusia ni Hübner (cabbage looper) andTuta absoluta Meyrick (tomato leafminer)). Compounds of the inventionalso have commercially significant activity on members from the orderHomoptera including: Acyrthisiphon pisum Harris (pea aphid), Aphiscraccivora Koch (cowpea aphid), Aphisfabae Scopoli (black bean aphid),Aphis gossypii Glover (cotton aphid, melon aphid), Aphis pomi De Geer(apple aphid), Aphis spiraecola Patch (spirea aphid), Aulacorthum solaniKaltenbach (foxglove aphid), Chaetosiphon fragaefolii Cockerell(strawberry aphid), Diuraphis noxia Kurdjumov/Mordvilko (Russian wheataphid), Dysaphis plantaginea Paaserini (rosy apple aphid), Eriosomalanigerum Hausmann (woolly apple aphid), Hyalopterus pruni Geoffroy(mealy plum aphid), Lipaphis erysimi Kaltenbach (turnip aphid),Metopolophium dirrhodum Walker (cereal aphid), Macrosipum euphorbiaeThomas (potato aphid), Myzus persicae Sulzer (peach-potato aphid, greenpeach aphid), Nasonovia ribisnigri Mosley (lettuce aphid), Pemphigusspp. (root aphids and gall aphids), Rhopalosiphum maidis Fitch (cornleaf aphid), Rhopalosiphum padi L. (bird cherry-oat aphid), Schizaphisgraminum Rondani (greenbug), Sitobion avenae Fabricius (English grainaphid), Therioaphis maculata Buckton (spotted alfalfa aphid), Toxopteraaurantii Boyer de Fonscolombe (black citrus aphid), and Toxopteracitricida Kirkaldy (brown citrus aphid); Adelges spp. (adelgids);Phylloxera devastatrix Pergande (pecan phylloxera); Bemisia tabaciGennadius (tobacco whitefly, sweetpotato whitefly), Bemisia argentifoliiBellows & Perring (silverleaf whitefly), Dialeurodes citri Ashmead(citrus whitefly) and Trialeurodes vaporariorum Westwood (greenhousewhitefly); Empoasca fabae Harris (potato leafhopper), Laodelphaxstriatellus Fallen (smaller brown planthopper), Macrolestesquadrilineatus Forbes (aster leafhopper), Nephotettix cinticeps Uhler(green leafhopper), Nephotettix nigropictus Stal (rice leafhopper),Nilaparvata lugens St{dot over (a)}l (brown planthopper), Peregrinusmaidis Ashmead (corn planthopper), Sogatella furcifera Horvath(white-backed planthopper), Sogatodes orizicola Muir (rice delphacid),Typhlocyba pomaria McAtee white apple leafhopper, Erythroneoura spp.(grape leafhoppers); Magicidada septendecim L. (periodical cicada);Icerya purchasi Maskell (cottony cushion scale), Quadraspidiotusperniciosus Comstock (San Jose scale); Planococcus citri Risso (citrusmealybug); Pseudococcus spp. (other mealybug complex); Cacopsyllapyricola Foerster (pear psylla), Trioza diospyri Ashmead (persimmonpsylla). These compounds also have activity on members from the orderHemiptera including: Acrosternum hilare Say (green stink bug), Anasatristis De Geer (squash bug), Blissus leucopterus leucopterus Say(chinch bug), Corythuca gossypli Fabricius (cotton lace bug),Cyrtopeltis modesta Distant (tomato bug), Dysdercus suturellusHerrich-Schäffer (cotton stainer), Euchistus servus Say (brown stinkbug), Euchistus variolarius Palisot de Beauvois (one-spotted stink bug),Graptosthetus spp. (complex of seed bugs), Leptoglossus corculus Say(leaf-footed pine seed bug), Lygus lineolaris Palisot de Beauvois(tarnished plant bug), Nezara viridula L. (southern green stink bug),Oebalus pugnax Fabricius (rice stink bug), Oncopeltus fasciatus Dallas(large milkweed bug), Pseudatomoscelis seriatus Reuter (cottonfleahopper). Other insect orders controlled by compounds of theinvention include Thysanoptera (e.g., Frankliniella occidentalisPergande (western flower thrip), Scirthothrips citri Moulton (citrusthrip), Sericothnips variabilis Beach (soybean thrip), and Thrips tabaciLindeman (onion thrip); and the order Coleoptera (e.g., Leptinotarsadecemlineata Say (Colorado potato beetle), Epilachna varivestis Mulsant(Mexican bean beetle) and wireworms of the genera Agriotes, Athous orLimonius).

[0250] The method of this invention is applicable to virtually all plantspecies. Seeds that can be treated, include for example, wheat (Triticumaestivum L.), durum wheat (Triticum durum Desf.), barley (Hordeumvulgare L.) oat (Avena sativa L.), rye (Secale cereale L.), maize (Zeamays L.), sorghum (Sorghum vulgare Pers.), rice (Oryza sativa L.), wildrice (Zizania aquatica L.), cotton (Gossypium barbadense L. and G.hirsutum L.), flax (Linum usitatissimum L.), sunflower (Helianthusannuus L.), soybean (Glycine max Merr.), garden bean (Phaseolus vulgarisL.), lima bean (Phaseolus limensis Macf.), broad bean (Vicia faba L.),garden pea (Pisum sativum L.), peanut (Arachis hypogaea L.), alfalfa(Medicago sativa L.), beet (Beta vulgaris L.), garden lettuce (Lactucasativa L.), rapeseed (Brassica rapa L. and B. napus L.), cole crops suchas cabbage, cauliflower and broccoli (Brassica oleracea L.), turnip(Brassica rapa L.), leaf (oriental) mustard (Brassica juncea Coss.),black mustard (Brassica nigra Koch), tomato (Lycopersicon esculentumMill.), potato (Solanum tuberosum L.), pepper (Capsicum frutescens L.),eggplant (Solanum melongena L.), tobacco (Nicotiana tabacum), cucumber(Cucumis sativus L.), muskmelon (Cucumis melo L.), watermelon (Citrullusvulgaris Schrad.), squash (Curcurbita pepo L., C. moschata Duchesne. andC. maxima Duchesne.), carrot (Daucus carota L.), zinnia (Zinnia elegansJacq.), cosmos (e.g., Cosmos bipinnatus Cav.), chrysanthemum(Chrysanthemum spp.), sweet scabious (Scabiosa atropurpurea L.),snapdragon (Antirrhinum majus L.), gerbera (Gerbera jamesonii Bolus),babys-breath (Gypsophila paniculata L., G. repens L. and G. elegansBieb.), statice (e.g., Limonium sinuatum Mill., L. sinense Kuntze.),blazing star (e.g., Liatris spicata Willd., L. pycnostachya Michx., L.scariosa Willd.), lisianthus (e.g., Eustoma grandiflorum (Raf.) Shinn),yarrow (e.g., Achillea filipendulina Lam., A. millefolium L.), marigold(e.g., Tagetes patula L., T. erecta L.), pansy (e.g., Viola cornuta L.,V. tricolor L.), impatiens (e.g., Impatiens balsamina L.) petunia(Petunia spp.), geranium (Geranium spp.) and coleus (e.g., Solenostemonscutellarioides (L.) Codd). Not only seeds, but also rhizomes, tubers,bulbs or corms, including viable cuttings thereof, can be treatedaccording to the invention from, for example, potato (Solanum tuberosumL.), sweet potato (Ipomoea batatas L.), yam (Dioscorea cayenensis Lam.and D. rotundata Poir.), garden onion (e.g., Allium cepa L.), tulip(Tulipa spp.), gladiolus (Gladiolus spp.), lily (Lilium spp.), narcissus(Narcissus spp.), dahlia (e.g., Dahliapinnata Cav.), iris (Irisgermanica L. and other species), crocus (Crocus spp.), anemone (Anemonespp.), hyacinth (Hyacinth spp.), grapehyacinth (Muscari spp.), freesia(e.g., Freesia refracta Klatt., F. armstrongii W. Wats), ornamentalonion (Allium spp.), wood-sorrel (Oxalis spp.), squil (Scilla peruvianaL. and other species), cyclamen (Cyclamen persicum Mill. and otherspecies), glory-of-the-snow (Chionodoxa luciliae Boiss. and otherspecies), striped squill (Puschkinia scilloides Adams), calla lily(Zantedeschia aethiopica Spreng., Z. elliottiana Engler and otherspecies), gloxinia (Sinnigia speciosa Benth. & Hook.) and tuberousbegonia (Begonia tuberhybrida Voss.). Stem cuttings can be treatedaccording to this invention include those from such plants as sugarcane(Saccharum officinarum L.), carnation (Dianthus caryophyllus L.),florists chrysanthemum (Chrysanthemum mortifolium Ramat.), begonia(Begonia spp.), geranium (Geranium spp.), coleus (e.g., Solenostemonscutellarioides (L.) Codd) and poinsettia (Euphorbia pulcherrimaWilld.). Leaf cuttings which can be treated according to this inventioninclude those from begonia (Begonia spp.), african-violet (e.g.,Saintpaulia ionantha Wendl.) and sedum (Sedum spp.). The above recitedcereal, vegetable, ornamental (including flower) and fruit crops areillustrative, and should not be considered limiting in any way. Forreason of invertebrate pest control spectrum and economic importance,seed treatments of cotton, maize, soybean and rice, and tuber and bulbtreatments of potato, sweet potato, garden onion, tulip, daffodil,crocus and hyacinth are preferred embodiments of the invention.

[0251] The locus of the propagules can be treated with a Formula Icompound by many different methods. All that is needed is for abiologically effective amount of a Formula I compound to be applied onor sufficiently close to the propagule so that it can be absorbed by thepropagule. The Formula I compound can be applied by such methods asdrenching the growing medium including a propagule with a solution ordispersion of a Formula I compound, mixing a Formula I compound withgrowing medium and planting a propagule in the treated growing medium(e.g., nursery box treatments), or various forms of propagule treatmentswhereby a Formula I compound is applied to a propagule before it isplanted in a growing medium.

[0252] In these methods the Formula I compound will generally be used asa formulation or composition with an agriculturally suitable carriercomprising at least one of a liquid diluent, a solid diluent or asurfactant. A wide variety of formulations are suitable for thisinvention, the most suitable types of formulations depend upon themethod of application. As is well known to those skilled in the art, thepurpose of formulation is to provide a safe and convenient means oftransporting, measuring and dispensing the crop protection chemical andalso to optimize its bioefficacy.

[0253] Depending on the method of application useful formulationsinclude liquids such as solutions (including emulsifiable concentrates),suspensions, emulsions (including microemulsions and/or suspoemulsions)and the like which optionally can be thickened into gels. Usefulformulations further include solids such as dusts, powders, granules,pellets, tablets, films, and the like which can be water-dispersible(“wettable”) or water-soluble. Active ingredient can be(micro)encapsulated and further formed into a suspension or solidformulation; alternatively the entire formulation of active ingredientcan be encapsulated (or “overcoated”). Encapsulation can control ordelay release of the active ingredient. Sprayable formulations can beextended in suitable media and used at spray volumes from about one toseveral hundred liters per hectare. High-strength compositions areprimarily used as intermediates for further formulation.

[0254] The formulations will typically contain effective amounts ofactive ingredient, diluent and surfactant within the followingapproximate ranges that add up to 100 percent by weight. Weight PercentActive Ingredient Diluent Surfactant Water-Dispersible and 5-90  0-941-15 Water-soluble Granules, Tablets and Powders. Suspensions,Emulsions, 5-50 40-95 0-15 Solutions (including EmulsifiableConcentrates) Dusts 1-25 70-99 0-5  Granules and Pellets 0.01-99     5-99.99 0-15 High Strength Compositions 90-99   0-10 0-2 

[0255] Typical solid diluents are described in Watkins et al., Handbookof Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books,Caldwell, N.J. Typical liquid diluents are described in Marsden,Solvents Guide, 2nd Ed., Interscience, N.Y., 1950. McCutcheon'sEmulsifiers and Detergents and McCutcheon's Functional Materials (NorthAmerica and International Editions, 2001), The Manufacturing ConfectionPubl. Co., Glen Rock, N.J., as well as Sisely and Wood, Encyclopedia ofSurface Active Agents, Chemical Publ. Co., Inc., N.Y., 1964, listsurfactants and recommended uses. All formulations can contain minoramounts of additives to reduce foam, caking, corrosion, microbiologicalgrowth and the like, or thickeners to increase viscosity.

[0256] Surfactants include, for example, ethoxylated alcohols,ethoxylated alkylphenols, ethoxylated sorbitan fatty acid esters,ethoxylated amines, ethoxylated fatty acids, esters and oils, dialkylsulfosuccinates, alkyl sulfates, alkylaryl sulfonates, organosilicones,N,N-dialkyltaurates, glycol esters, phosphate esters, lignin sulfonates,naphthalene sulfonate formaldehyde condensates, polycarboxylates, andblock polymers including polyoxy-ethylene/polyoxypropylene blockcopolymers. Solid diluents include, for example, clays such asbentonite, montmorillonite, attapulgite and kaolin, starch, sugar,silica, talc, diatomaceous earth, urea, calcium carbonate, sodiumcarbonate and bicarbonate, and sodium sulfate. Liquid diluents include,for example, water, N,N-dimethylformamide, dimethyl sulfoxide,N-alkylpyrrolidone, ethylene glycol, polypropylene glycol propylenecarbonate, dibasic esters, paraffins, alkylbenzenes, alkylnaphthalenes,oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed,soybean, rape-seed and coconut, fatty acid esters, ketones such ascyclohexanone, 2-heptanone, isophorone and4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol,cyclohexanol, decanol, benzyl and tetrahydrofurfuryl alcohol.

[0257] Solutions, including emulsifiable concentrates, can be preparedby simply mixing the ingredients. Dusts and powders can be prepared byblending and, usually, grinding as in a hammer mill or fluid-energymill. Suspensions are usually prepared by wet-milling; see, for example,U.S. Pat. No. 3,060,084. Granules and pellets can be prepared byspraying the active material upon preformed granular carriers or byagglomeration techniques. See Browning, “Agglomeration”, ChemicalEngineering, Dec. 4, 1967, pp 147-48, Perry's Chemical Engineer'sHandbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 andfollowing, and PCT Publication WO 91/13546. Pellets can be prepared asdescribed in U.S. Pat. No. 4,172,714. Water-dispersible andwater-soluble granules can be prepared as taught in U.S. Pat. No.4,144,050, U.S. Pat. No. 3,920,442 and DE 3,246,493. Tablets can beprepared as taught in U.S. Pat. No. 5,180,587, U.S. Pat. No. 5,232,701and U.S. Pat. No. 5,208,030. Films can be prepared as taught in GB2,095,558 and U.S. Pat. No. 3,299,566.

[0258] For further information regarding the art of formulation, see T.S. Woods, “The Formulator's Toolbox—Product Forms for Modem Agriculture”in Pesticide Chemistry and Bioscience, The Food-Environment Challenge,T. Brooks and T. R. Roberts, Eds., Proceedings of the 9th InternationalCongress on Pesticide Chemistry, The Royal Society of Chemistry,Cambridge, 1999, pp. 120-133. See also U.S. Pat. No. 3,235,361, Col. 6,line 16 through Col. 7, line 19 and Examples 10-41; U.S. Pat. No.3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12,15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182;U.S. Pat. No. 2,891,855, Col. 3, line 66 through Col. 5, line 17 andExamples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons,Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook,8th Ed., Blackwell Scientific Publications, Oxford, 1989.

[0259] A propagule or a plant grown therefrom can be protected from aninvertebrate pest according to this invention by a method comprisingcontacting the propagule or the locus of the propagule with acomposition comprising a biologically effective amount of a compound ofFormula I, an N-oxide thereof or an agriculturally suitable saltthereof. The invention includes a propagule contacted with a compositioncomprising a biologically effective amount a compound of Formula I, itsN-oxide or an agriculturally suitable salt thereof and an effectiveamount of at least one other biologically active compound or agent. Thecompositions used for treating propagules (or plant grown therefrom)according to this invention can also comprise (besides the Formula Icomponent) an effective amount of one or more other biologically activecompounds or agents. Suitable additional compounds or agents includeinsecticides, fungicides, nematocides, bactericides, acaricides, growthregulators such as rooting stimulants, chemosterilants, semiochemicals,repellents, attractants, pheromones, feeding stimulants, otherbiologically active compounds or entomopathogenic bacteria, virus orfungi to form a multi-component pesticide giving an even broaderspectrum of agricultural utility. Examples of such biologically activecompounds or agents with which compounds of this invention can beformulated are: insecticides such as abamectin, acephate, acetamiprid,amidoflumet (S-1955), avermectin, azadirachtin, azinphos-methyl,bifenthrin, binfenazate, buprofezin, carbofuran, chlorfenapyr,chlorfluazuron, chlorpyrifos, chlorpyrifos-methyl, chromafenozide,clothianidin, cyfluthrin, beta-cyfluthrin, cyhalothrin,lambda-cyhalothrin, cypermethrin, cyromazine, deltamethrin,diafenthiuron, diazinon, diflubenzuron, dimethoate, diofenolan,emamectin, endosulfan, esfenvalerate, ethiprole, fenothicarb,fenoxycarb, fenpropathrin, fenproximate, fenvalerate, fipronil,flonicamid, flucythrinate, tau-fluvalinate, flufenerim (UR-50701),flufenoxuron, fonophos, halofenozide, hexaflumuron, imidacloprid,indoxacarb, isofenphos, lufenuron, malathion, metaldehyde,methamidophos, methidathion, methomyl, methoprene, methoxychlor,monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron(XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate,phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine,pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060),sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos,tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb,thiosultap-sodium, tralomethrin, trichlorfon and triflumuron; fungicidessuch as acibenzolar, azoxystrobin, benomyl, blasticidin-S, Bordeauxmixture (tribasic copper sulfate), bromuconazole, carpropamid, captafol,captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride,copper salts, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,(S)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one(RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin,fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil,flumetover (RPA 403397), flumorflflumorlin (SYP-L190), fluoxastrobin(HEC 5725), fluquinconazole, flusilazole, flutolanil, flutriafol,folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658),hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane,kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil,metalaxyl metconazole, metominostrobin/fenominostrobin (SSF-126),metrafenone (AC 375839), myclobutanil, neo-asozin (fenicmethanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl,penconazole, pencycuron, probenazole, prochloraz, propamocarb,propiconazole, proquinazid (OPX-KQ926), prothioconazole (JAU 6476),pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen,spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon,triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycinand vinclozolin; nematocides such as aldicarb, oxamyl and fenamiphos;bactericides such as streptomycin; acaricides such as amitraz,chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor,etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate,hexythiazox, propargite, pyridaben and tebufenpyrad; and biologicalagents such as Bacillus thuringiensis including ssp. aizawai andkurstaki, Bacillus thuringiensis delta endotoxin, baculovirus, andentomopathogenic bacteria, virus and fungi. A general reference forthese agricultural protectants is The Pesticide Manual, 12th Edition, C.D. S. Tomlin, Ed., British Crop Protection Council, Farnham, Surrey,U.K., 2000.

[0260] Preferred insecticides and acaricides for mixing with Formula Icompounds include pyrethroids such as cypermethrin, cyhalothrin,cyfluthrin and beta-cyfluthrin, esfenvalerate, fenvalerate andtralomethrin; carbamates such as fenothicarb, methomyl, oxamyl andthiodicarb; neonicotinoids such as clothianidin, imidacloprid andthiacloprid; neuronal sodium channel blockers such as indoxacarb,insecticidal macrocyclic lactones such as spinosad, abamectin,avermectin and emamectin; γ-aminobutyric acid (GABA) antagonists such asendosulfan, ethiprole and fipronil; insecticidal ureas such asflufenoxuron and triflumuron; juvenile hormone mimics such as diofenolanand pyriproxyfen; pymetrozine; and amitraz. Preferred biological agentsfor mixing with compounds of this invention include Bacillusthuringiensis and Bacillus thuringiensis delta endotoxin as well asnaturally occurring and genetically modified viral insecticidesincluding members of the family Baculoviridae as well as entomophagousfungi.

[0261] Preferred plant growth regulants for mixing with the Formula Icompounds in compositions for treating stem cuttings are1H-indole-3-acetic acid, 1H-indole-3-butanoic acid and1-naphthaleneacetic acid and their agriculturally suitable salt, esterand amide derivatives, such as 1-napthaleneacetamide. Preferredfungicides for mixing with the Formula I compounds include fungicidesuseful as seed treatments such as thiram, maneb, mancozeb and captan.

[0262] In the following Examples, all percentages are by weight and allformulations are prepared in conventional ways. Compound numbers referto compounds in Index Table A.

EXAMPLE A

[0263] Wettable Powder Compound 208 65.0% dodecylphenol polyethyleneglycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate6.0% montmorillonite (calcined) 23.0%.

EXAMPLE B

[0264] Granule Compound 486 10.0%  attapulgite granules (low volatilematter, 90.0%. 0.71/0.30 mm; U.S.S. No. 25-50 sieves)

EXAMPLE C

[0265] Extruded Pellet Compound 509 25.0% anhydrous sodium sulfate 10.0%crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0%calcium/magnesium bentonite 59.0%.

EXAMPLE D

[0266] Emulsifiable Concentrate Compound 516 20.0% blend of oil solublesulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.

[0267] For growing-medium drenches, the formulation needs to provide theFormula I compound, generally after dilution with water, in solution oras particles small enough to remain dispersed in the liquid.Water-dispersible or soluble powders, granules, tablets, emulsifiableconcentrates, aqueous suspension concentrates and the like areformulations suitable for aqueous drenches of growing media. Drenchesare most satisfactory for treating growing media that have relativelyhigh porosity, such as light soils or artificial growing mediumcomprising porous materials such as peat moss, perlite, vermiculite andthe like. The drench liquid comprising the Formula I compound can alsobe added to a liquid growing medium (i.e. hydroponics), which causes theFormula I compound to become part of the liquid growing medium. Oneskilled the art will appreciate that the amount of Formula I compoundneeded in the drench liquid for invertebrate pest control efficacy (i.e.biologically effective amount) will vary with the type of propagule, theFormula I compound, the duration and extent of plant protection desired,the invertebrate pests to be controlled and environmental factors. Theconcentration of Formula I compound in the drench liquid is generallybetween about 0.01 ppm and 10,000 ppm, more typically between about 1ppm and 100 ppm. One skilled in the art can easily determine thebiologically effective concentration necessary for the desired level ofphytophagous invertebrate pest control.

[0268] For treating a growing medium a Formula I compound can also beapplied by mixing it as a dry powder or granule formulation with thegrowing medium. Because this method of application does not requirefirst dispersing or dissolving in water, the dry powder or granuleformulations need not be highly dispersible or soluble. While in anursery box the entire body of growing medium may be treated, in anagricultural field only the soil in the vicinity of the propagule istypically treated for environmental and cost reasons. To minimizeapplication effort and expense, a formulation of Formula I compound ismost efficiently applied concurrently with propagule planting (e.g.,seeding). For in-furrow application, the Formula I formulation (mostconveniently a granule formulation) is applied directly behind theplantershoe. For T-band application, the Formula I formulation isapplied in a band over the row behind the planter shoe and behind orusually in front of the press wheel. One skilled the art will appreciatethat the amount of Formula I compound needed in the growing medium locusfor invertebrate pest control efficacy (i.e. biologically effectiveamount) will vary with the type of propagule, the Formula I compound,the duration and extent of plant protection desired, the invertebratepests to be controlled and environmental factors. The concentration ofFormula I compound in the growing medium locus of the propagule isgenerally between about 0.0001 ppm and 100 ppm, more typically betweenabout 0.01 ppm and 10 ppm. One skilled in the art can easily determinethe biologically effective amount necessary for the desired level ofphytophagous invertebrate pest control.

[0269] A propagule can be directly treated by soaking it in a solutionor dispersion of a Formula I compound. Although this application methodis useful for propagules of all types, treatment of large seeds (e.g.,having a mean diameter of at least 3 mm) is more effective thantreatment of small seeds for providing invertebrate pest controlprotection to the developing plant. Treatment of propagules such astubers, bulbs, corms, rhizomes and stem and leaf cuttings also canprovide effective treatment of the developing plant in addition to thepropagule. The formulations useful for growing-medium drenches aregenerally also useful for soaking treatments. The soaking mediumcomprises a nonphytotoxic liquid, generally water-based although it maycontain nonphytotoxic amounts of other solvents such as methanol,ethanol, isopropanol, ethylene glycol, propylene glycol, propylenecarbonate, benzyl alcohol, dibasic esters, acetone, methyl acetate,ethyl acetate, cyclohexanone, dimethylsulfoxide and N-methylpyrrolidone,which may be useful for enhancing solubility of the Formula I compoundand penetration into the propagule. A surfactant can facilitate wettingof the propagule and penetration of the Formula I compound. One skilledthe art will appreciate that the amount of Formula I compound needed inthe soaking medium for invertebrate pest control efficacy (i.e.biologically effective amount) will vary with the type of propagule, theFormula I compound, the duration and extent of plant protection desired,the invertebrate pests to be controlled and environmental factors. Theconcentration of Formula I compound in the soaking liquid is generallybetween about 0.01 ppm and 10,000 ppm, more typically between about 1ppm and 100 ppm. One skilled in the art can easily determine thebiologically effective concentration necessary for the desired level ofphytophagous invertebrate pest control. The soaking time can vary from 1minute to 1 day or even longer. Indeed the propagule can remain in thetreatment liquid while it is germinating or sprouting (e.g., sproutingof rice seeds prior to direct seeding). As shoot and root emerge throughthe testa (seed coat), the shoot and root directly contact the solutioncomprising the Formula I compound. For treatment of sprouting seeds oflarge-seeded crops such as rice, treatment times of about 8 to 48 hours,e.g., about 24 hours, is typical. Shorter times are most useful fortreating small seeds.

[0270] A propagule can also be coated with a composition comprising abiologically effective amount of a Formula I compound. The coatings ofthe invention are capable of effecting a slow release of a Formula Icompound by diffusion into the propagule and surrounding medium.Coatings include dry dusts or powders adhering to the propagule byaction of a sticking agent such as methylcellulose or gum arabic.Coatings can also be prepared from suspension concentrates,water-dispersible powders or emulsions that are suspended in water,sprayed on the propagule in a tumbling device and then dried. Formula Icompounds that are dissolved in the solvent can be sprayed on thetumbling propagule and the solvent then evaporated. Such compositionspreferably include ingredients promoting adhesion of the coating to thepropagule. The compositions may also contain surfactants promotingwetting of the propagule. Solvents used must not be phytotoxic to thepropagule; generally water is used, but other volatile solvents with lowphytotoxicity such as methanol, ethanol, methyl acetate, ethyl acetate,acetone, etc. may be employed alone or in combination. Volatile solventsare those with a normal boiling point less than about 100° C. Dryingmust be conducted in a way not to injure the propagule or inducepremature germination or sprouting.

[0271] The thickness of coatings can vary from adhering dusts to thinfilms to pellet layers about 0.5 to 5 mm thick. Propagule coatings ofthis invention can comprise more than one adhering layers, only one ofwhich need comprise a Formula I compound. Generally pellets are mostsatisfactory for small seeds, because their ability to provide abiologically effective amount of a Formula I compound is not limited bythe surface area of the seed, and pelleting small seeds also facilitatesseed transfer and planting operations. Because of their larger size andsurface area, large seeds and bulbs, tubers, corms and rhizomes andtheir viable cuttings are generally not pelleted, but instead coatedwith powders or thin films.

[0272] Propagules contacted with compounds of Formula I in accordance tothis invention include seeds. Suitable seeds include seeds of wheat,durum wheat, barley, oat, rye, maize, sorghum, rice, wild rice, cotton,flax, sunflower, soybean, garden bean, lima bean, broad bean, gardenpea, peanut, alfalfa, beet, garden lettuce, rapeseed, cole crop, turnip,leaf mustard, black mustard, tomato, potato, pepper, eggplant, tobacco,cucumber, muskmelon, watermelon, squash, carrot, zinnia, cosmos,chrysanthemum, sweet scabious, snapdragon, gerbera, babys-breath,statice, blazing star, lisianthus, yarrow, marigold, pansy, impatiens,petunia, geranium and coleus. Of note are seeds of cotton, maize,soybean and rice. Propagules contacted with compounds of Formula I inaccordance to this invention also include rhizomes, tubers, bulbs orcorms, or viable divisions thereof Suitable rhizomes, tubers, bulbs andcorms, or viable divisions thereof include those of potato, sweetpotato, yam, garden onion, tulip, gladiolus, lily, narcissus, dahlia,iris, crocus, anemone, hyacinth, grape-hyacinth, freesia, ornamentalonion, wood-sorrel, squill, cyclamen, glory-of-the-snow, striped squill,calla lily, gloxinia and tuberous begonia. Of note are rhizomes, tubers,bulbs and corms, or viable division thereof of potato, sweet potato,garden onion, tulip, daffodil, crocus and hyacinth. Propagules contactedwith compounds of Formula I in accordance to this invention also includestems and leaf cuttings.

[0273] One embodiment of a propagule contacted with a Formula I compoundis a propagule coated with a composition comprising a compound ofFormula I, its N-oxide or an agriculturally suitable salt thereof and afilm former or adhesive agent. Compositions of this invention whichcomprise a biologically effective amount of a compound of Formula I, itsN-oxide or an agriculturally suitable salt thereof and a film former oradhesive agent, can further comprise an effective amount of at least oneadditional biologically active compound or agent. Of note arecompositions comprising (in addition to the Formula I component and thefilm former or adhesive agent) an arthropodicides of the groupconsisting of pyrethroids, carbamates, neonicotinoids, neuronal sodiumchannel blockers, insecticidal macrocyclic lactones, γ-aminobutyric acid(GABA) antagonists, insecticidal ureas and juvenile hormone mimics. Alsoof note are compositions comprising (in addition to the Formula Icomponent and the film former or adhesive agent) at least one additionalbiologically active compound or agent selected from the group consistingof abamectin, acephate, acetamiprid, amidoflumet (S-1955), avermectin,azadirachtin, azinphos-methyl, bifenthrin, binfenazate, buprofezin,carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos,chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin,beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin,cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron,dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole,fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate,fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerim(UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron,imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaldehyde,methamidophos, methidathion, methomyl, methoprene, methoxychlor,monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron(XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate,phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine,pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060),sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos,tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb,thiosultap-sodium, tralomethrin, trichlorfon and triflumuron, aldicarb,oxamyl, fenamiphos, amitraz, chinomethionat, chlorobenzilate, cyhexatin,dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide,fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben,tebufenpyrad; and biological agents such as Bacillus thuringiensisincluding ssp. aizawai and kurstaki, Bacillus thuringiensis deltaendotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.Also of note are compositions comprising (in addition to the Formula Icomponent and the film former or adhesive agent) at least one additionalbiologically active compound or agent selected from fingicides of thegroup consisting of acibenzolar, azoxystrobin, benomyl, blasticidin-S,Bordeaux mixture (tribasic copper sulfate), bromuconazole, carpropamid,captafol, captan, carbendazim, chloroneb, chlorothalonil, copperoxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazole,cyprodinil,(S)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one(RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin,fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil,flumetover (RPA 403397), flumorflflumorlin (SYP-L190), fluoxastrobin(HEC 5725), fluquinconazole, flusilazole, flutolanil, flutriafol,folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658),hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane,kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil,metalaxyl, metconazole, metominostrobin/fenominostrobin (SSF-126),metrafenone (AC 375839), myclobutanil, neo-asozin (ferricmethanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl,penconazole, pencycuron, probenazole, prochloraz, propamocarb,propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU 6476),pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen,spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon,triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycinand vinclozolin (especially compositions wherein the at least oneadditional biologically active compound or agent is selected fromfungicides in the group consisting of thiram, maneb, mancozeb andcaptan).

[0274] Generally a propagule coating of the invention comprises acompound of Formula I, a film former or sticking agent. The coating mayfurther comprise formulation aids such as a dispersant, a surfactant, acarrier and optionally an antifoam and dye. One skilled the art willappreciate that the amount of Formula I compound needed in the coatingfor invertebrate pest control efficacy (i.e. biologically effectiveamount) will vary with the type of propagule, the Formula I compound,the duration and extent of plant protection desired, the invertebratepests to be controlled and environmental factors. The coating needs tonot inhibit germination or sprouting of the propagule and should beconsistently efficacious in reducing plant injury during theplant-injury-causing phase of the target invertebrate pest's life cycle.A coating comprising sufficient Formula I compound can provideinvertebrate pest control protection for up to about 120 days or evenlonger. Generally the amount of Formula I compound ranges from about0.001 to 50% of the weight of the propagule, for seeds more often in therange of about 0.01 to 50% of the seed weight, and most typically forlarge seeds in the range of about 0.1 to 10% of the seed weight.However, larger amounts up to about 100% or more are useful,particularly for pelleting small seed for extended invertebrate pestcontrol protection. For propagules such as bulbs, tubers, corms andrhizomes and their viable cuttings, and stem and leaf cuttings,generally the amount of Formula I compound ranges from about 0.001 to 5%of the propagule weight, with the higher percentages used for smallerpropagules. One skilled in the art can easily determine the biologicallyeffective amount necessary for the desired level of phytophagousinvertebrate pest control.

[0275] The film former or adhesive agent component of the propagulecoating is composed preferably of an adhesive polymer that may benatural or synthetic and is without phytotoxic effect on the propaguleto be coated. The film former or sticking agent may be selected frompolyvinyl acetates, polyvinyl acetate copolymers, hydrolyzed polyvinylacetates, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylalcohols, polyvinyl alcohol copolymers, polyvinyl methyl ether,polyvinyl methyl ether-maleic anhydride copolymer, waxes, latexpolymers, celluloses including ethylcelluloses and methylcelluloses,hydroxy-methylcelluloses, hydroxypropylcellulose,hydroxymethylpropylcelluloses, polyvinyl-pyrrolidones, alginates,dextrins, malto-dextins, polysaccharides, fats, oils, proteins, karayagum, jaguar gum, tragacanth gum, polysaccharide gums, mucilage, gumarabics, shellacs, vinylidene chloride polymers and copolymers,soybean-based protein polymers and copolymers, lignosulfonates, acryliccopolymers, starches, polyvinylacrylates, zeins, gelatin,carboxymethylcellulose, chitosan, polyethylene oxide, acrylimidepolymers and copolymers, polyhydroxyethyl acrylate, methylacrylimidemonomers, alginate, ethylcellulose, polychloroprene and syrups ormixtures thereof. Preferred film formers and adhesive agents includepolymers and copolymers of vinyl acetate, polyvinylpyrrohdone-vinylacetate copolymer and water-soluble waxes. Particularly preferred arepolyvinylpyrrolidone-vinyl acetate copolymers and water-soluble waxes.The above-identified polymers include those known in the art and forexample some are identified as Agrimer® VA 6 and Licowax® KST. Theamount of film former or sticking agent in the formulation is generallyin the range of about 0.001 to 100% of the weight of the propagule. Forlarge seeds the amount of film former or sticking agent is typically inthe range of about 0.05 to 5% of the seed weight; for small seeds theamount is typically in the range of about 1 to 100%, but can be greaterthan 100% of seed weight in pelleting. For other propagules the amountof film former or sticking agent is typically in the range of 0.001 to2% of the propagule weight.

[0276] Materials known as formulation aids may also be used in propaguletreatment coatings of the invention for the invertebrate pest controland are well known to those skilled in the art. Formulation aids assistin the production or process of propagule treatment and include but arenot limited to dispersants, surfactants, carriers, antifoams and dyes.Useful dispersants can include highly water-soluble anionic surfactantslike Borresperse™ CA, Morwet® D425 and the like. Useful surfactants caninclude highly water-soluble nonionic surfactants like Pluronic® F108,Brij® 78 and the like. Useful carriers can include liquids like waterand oils which are water soluble such as alcohols. Useful carriers canalso include fillers like woodflours, clays, activated carbon,diatomaceous earth, fine-grain inorganic solids, calcium carbonate andthe like. Clays and inorganic solids which may be used include calciumbentonite, kaolin, china clay, talc, perlite, mica, vermiculite,silicas, quartz powder, montmorillonite and mixtures thereof. Antifoamscan include water dispersible liquids comprising polyorganic siloxaneslike Rhodorsil® 416. Dyes can include water dispersible liquid colorantcompositions like Pro-lzed® Colorant Red. One skilled in the art willappreciate that this is a non-exhaustive list of formulation aids andthat other recognized materials may be used depending on the propaguleto be coated and the compound of Formula I used in the coating. Suitableexamples of formulation aids include those listed herein and thoselisted in McCutcheon's 2001, Volume 2: Functional Materials, publishedby MC Publishing Company. The amount of formulation aids used may vary,but generally the weight of the components will be in the range of about0.001 to 10000% of the propagule weight, with the percentages above 100%being mainly used for pelleting small seed. For nonpelleted seedgenerally the amount of formulating aids is about 0.01 to 45% of theseed weight and typically about 0.1 to 15% of the seed weight. Forpropagules other than seeds, the amount of formulation aids generally isabout 0.001 to 10% of the propagule weight.

[0277] Conventional means of applying seed coatings may be used to carryout the coating of the invention. Dusts or powders may be applied bytumbling the propagule with a formulation comprising a Formula Icompound and a sticking agent to cause the dust or powder to adhere tothe propagule and not fall off during packaging or transportation. Dustsor powders can also be applied by adding the dust or powder directly tothe tumbling bed of propagules, followed by spraying a carrier liquidonto the seed and drying. Dusts and powders comprising a Formula Icompound can also be applied by treating (e.g., dipping) a least aportion of the propagule with a solvent such as water, optionallycomprising a sticking agent, and dipping the treated portion into asupply of the dry dust or powder. This method can be particularly usefulfor coating stem cuttings. Propagules can also be dipped intocompositions comprising Formula I formulations of wetted powders,solutions, suspoemulsions, emulfiable concentrates and emulsions inwater, and then dried or directly planted in the growing medium.Propagules such as bulbs, tubers, corms and rhizomes typically need onlya single coating layer to provide a biologically effective amount of aFormula I compound.

[0278] Propagules may also be coated by spraying a suspensionconcentrate directly into a tumbling bed of propagules and then dryingthe propagules. Alternatively, other formulation types like wettedpowders, solutions, suspoemulsions, emulsifiable concentrates andemulsions in water may be sprayed on the propagules. This process isparticularly useful for applying film coatings to seeds. Various coatingmachines and processes are available to one skilled in the art. Suitableprocesses include those listed in P. Kosters et al., Seed Treatment:Progress and Prospects, 1994 BCPC Monograph No. 57 and the referenceslisted therein. Three well-known techniques include the use of drumcoaters, fluidized bed techniques and spouted beds. Propagules such asseeds may be presized prior to coating. After coating the propagules aredried and then optionally sized by transfer to a sizing machine. Thesemachines are known in the art for example, a typical machine used whensizing corn (maize) seed in the industry.

[0279] For coating seed, the seed and coating material are mixed in anyvariety of conventional seed coating apparatus. The rate of rolling andapplication of coating depends upon the seed. For large oblong seedssuch as that of cotton, a satisfactory seed coating apparatus comprisesa rotating type pan with lifting vanes turned sufficient rpm to maintaina rolling action of the seed, facilitating uniform coverage. For seedcoating formulations applied as liquids, the seed coating must beapplied over sufficient time to allow drying to minimize clumping of theseed. Using forced air or heated forced air can allow increasing therate of application. One skilled in the art will also recognize thatthis process may be a batch or continuous process. As the name implies,a continuous process allows the seeds to flow continuously throughoutthe product run. New seeds enter the pan in a steady stream to replacecoated seeds exiting the pan.

[0280] The seed coating process of the present invention is not limitedto thin film coating and may also include seed pelleting. The pelletingprocess typically increases the seed weight from 2 to 100 times and canbe used to also improve the shape of the seed for use in mechanicalseeders. Pelleting compositions generally contain a solid diluent, whichis typically an insoluble particulate material, such as clay, groundlimestone, powdered silica, etc. to provide bulk in addition to a bindersuch as an artificial polymer (e.g., polyvinyl alcohol, hydrolyzedpolyvinyl acetates, polyvinyl methyl ether, polyvinyl methylether-maleic anhydride copolymer, and polyvinylpyrrolidinone) or naturalpolymer (e.g., alginates, karaya gum, jaguar gum, tragacanth gum,polysaccharide gum, mucilage). After sufficient layers have been builtup, the coat is dried and the pellets graded. A method for producingpellets is described in Agrow, The Seed Treatment Market, Chapter 3, PJBPublications Ltd., 1994.

[0281] For further description of composition components and processessuitable for the coating a propagule with a Formula I compound, see U.S.Pat. Nos. 4,443,637, 5,494,709, 5,527,760, 5,834,006, 5,849,320,5,876,739, 6,156,699, 6,199,318, 6,202,346 and 6,230,438 and EuropeanPatent Publication EP-1,078,563-A1.

[0282] The following Examples E-H illustrate the process of coatingseeds. Compound numbers refer to compounds in Index Table A.

EXAMPLE E Preparation of Cottonseed Batches Coated With CompositionComprising Compound 208 Step 1: Preparation of Flowable Suspensioncomprising Compound 208

[0283] A flowable suspension containing the ingredients listed in Table7 was prepared. TABLE 7 Amounts of Ingredients in Flowable SuspensionWt. % including Wt. % excluding Ingredient water water Compound 20815.60 52.28 Agrimer ® VA 6 5.00 16.76 Licowax ® KST 5.00 16.76Borresperse ™ CA 1.00 3.35 Pluronic ® F-108 1.00 3.35 Brij ® 78 2.006.70 Rhodorsil ® 416 0.20 0.67 Pro-lzed ® Colorant Red 0.04 0.13 Water70.16 —

[0284] Agrimer® VA 6 is a highly water-soluble, film-forming adhesivehaving a softening point of 106° C. comprising apolyvinylpyrrolidone-vinyl acetate copolymer and marketed byInternational Specialty Products (ISP). Licowax® KST is a highlywater-soluble, film-forming adhesive having a drop forming point of 59°C. comprising montan wax acid, polyethylene glycol ester and marketed byClariant. Borresperse™ CA is a highly water-soluble anionic dispersanthaving a softening point of 132° C. comprising de-sugared calciumlignosulfonate and marketed by Borregaard LignoTech. Pluronic® F-108 isa highly water-soluble, nonionic dispersant having a melting point of57° C. comprising polyoxypropylene-polyoxyethylene block copolymer andmarketed by BASF. Brij® 78 is a highly water-soluble, nonionicdispersant having a pour point of 38° C. comprising stearyl alcohol (POE20) and marketed by Uniqema. Rhodorsil® 416 is a water-dispersibleliquid antifoam agent comprising polyorganosiloxanes and emulsifyingagent and marketed by Rhodia. Pro-lzed® Colorant Red is awater-dispersible liquid colorant composition comprising a red colorant,kaolin clay and a nonionic surfactant and marketed by Gustafson.

[0285] A suspension carrier (253.20 g) was prepared by first dissolvingBrij® 78 (6.00 g) in warm water (210.48 g), followed by vigorouslymixing in Agrimer® VA 6 (15.00 g), Licowax® KST (15.00 g), Bornesperse™CA (3.00 g), Pluronic® F-108 (3.00 g), Brij® 78 (6.00 g), Rhodorsil® 416(0.6 g) and Pro-lzed® Colorant Red (0.12 g). Compound 208 (15.6 g) wasadded to a beaker, followed by a portion of the thoroughly mixedsuspension carrier (84.4 g), and a spatula was used to fold Compound 208into the suspension carrier. The mixture was then further homogenizedusing a Polytron high-speed rotor stator disperser (marketed by BrinkmanInstruments Inc., Cantiague Rd., Westbury, N.Y. 11590 U.S.A.) with a 10mm generator probe, which disintegrated aggregates of Compound 208.

[0286] The resulting slurry was then transferred to a running millcharged to 80% capacity with 0.5-mm, mono-sized, high-density ceramicmilling media and cooled by passing a chilled aqueous 33% ethyleneglycol solution through the cooling jacket of the milling chamber. Theslurry was recirculated through the milling chamber for 13 minutes withthe agitator spinning at 4300 rpm. The circulation pipe end was thenmoved from the mill feed funnel to a collection bottle to obtain thefinished pink, highly pourable flowable suspension (89.5 g).

[0287] The diameters of the micronized (milled) particles in thesuspension were analyzed using a laser diffraction instrument. Using theaverage of two measurements, the arithmetic mean particle diameter was2.03 μm, 90% of the particles were less than 5.21 μm diameter, 10% ofthe particles were less than 0.30 μm diameter, and the median particlediameter was

Step 2: Coating Cottonseed With Composition Comprising Compound 208

[0288] Cottonseed (Stoneville 4793 RR, 122.5 g) were added to astainless-steel pot (12 cm i.d., 11 cm depth) containing twocounter-opposing lifting vanes to lift the seed as the pot turns. Thepot was oriented at a 40 to 45° angle from horizontal and mechanicallyrotated at 640 rpm, which caused good mixing and tumbling action insidethe pot.

[0289] The flowable prepared in Step 1 was sprayed directly on thetumbling bed of seed with a supply air pressure of 10-11 psi (69-76 kPa)to produce fine droplets. By measuring the weight of the reservoir, theamount of flowable suspension sprayed on the seeds could be determined.With the seeds tumbling, the hand-held atomizer was pointed inside thepot to direct spray at the center of the tumbling bed of seed. Sprayingwas continued until the seed surfaces became tacky, causing the seeds toclump together. The atomizer was then shut off, and the seed coating wasquickly dried by blowing on the seed low-pressure air at roomtemperature from a nozzle mounted to direct airflow inside the pot. Theincreasing sound of tumbling seeds provided an audible signal that theseed coating was sufficiently dry. The drying airflow was then shut off,and spraying using the hand-held atomizer was resumed. The cycle ofspraying and drying was repeated until the desired amount of flowablesuspension had been applied to the seeds. The drying of the seed coatingwas then completed by exposure to a low flow of ambient air for 60hours.

[0290] The weights of Compound 208 applied to each of ten seeds fromeach batch was determined by macerating each seed in a bead mill andthen adding acetonitrile extraction solvent. The extracts werecentrifuged and aliquots of the supernate (supernatant liquid) werediluted 10,000:1 and then analyzed by LC/MS. The analysis results arelisted in Table 8. TABLE 8 Measurements for Cottonseed Coated withCompound 208 Composition Nominal Nominal Nominal Measurement 1% batch 2%batch 3% batch Weight of flowable suspension sprayed on 9.20 g 18.94 g30.21 g 122.5 g batch of seed Weight of treated seed batch after drying124.76 g 127.10 g 129.87 g Weight of dried coating on batch of treatedseed 2.26 g 4.60 g 7.37 g Average weight of one treated seed* 94 mg 101mg 115 mg Average weight of Compound 208 per seed* 1.2 mg 2.6 mg 4.4 mgAverage weight % of Compound 208 on coated 1.3% 2.6% 3.8% seed*

EXAMPLE F Preparation of Cornseed Batches Coated With CompositionComprising Compounds 208, 484, 486, 502, 509 or 515 Step 1: Preparationof 6 Flowable Suspensions Comprising Compounds 208, 484, 486, 502, 509or 515

[0291] Six flowable suspensions, each containing one of the six activeingredient compounds above, were prepared using the recipe as shown inTable 9 below. TABLE 9 Amounts of Ingredients in Flowable SuspensionsWt. % including Wt. % excluding Ingredient water water Compounds 208,484, 15.00 51.3 486, 502, 509 or 515 Agrimer ® VA 6 5.00 17.1 Licowax ®KST 5.00 17.1 Borresperse ™ CA 1.00 3.42 Pluronic ® F-108 1.00 3.42Brij ® 78 2.00 6.84 Rhodorsil ® 416 0.20 0.68 Pro-lzed ® Colorant Red0.04 0.14 Water 70.76 —

[0292] All the ingredients other than the active ingredient compoundsare described in Example E.

[0293] A flowable suspension of each compound was prepared by the methodas described in Example E, Step 1. The diameters (i.e. Dia. in Table 10)of the particles in the suspension were analyzed by the method alsodescribed in Example E, Step 1. The particle diameter distributionachieved after wet milling are shown in Table 10. TABLE 10 ParticleSizes of the 6 Flowable Suspensions Comound Compound Compound CompoundCompound Compound 208 484 486 509 502 515 Mean Particle Dia. =* 1.54 μm1.17 μm 0.92 μm 2.24 μm 1.03 μm 0.68 μm 90% of Particle Dia. <* 3.08 μm2.37 μm 2.04 μm 4.87 μm 2.30 μm 1.36 μm Median Particle Dia. 1.27 μm0.92 μm 0.59 μm 1.47 μm 0.67 μm 0.50 μm 10% of Particle Dia. <* 0.35 μm0.30 μm 0.27 μm 0.34 μm 0.27 μm 0.26 μm

Step 2: Coating Corn Seed With Separate Compositions ComprisingCompounds 208, 484, 486, 502, 509 or 515

[0294] Corn (maize) seed (Pioneer 3146 Lot #C92FA (Parent), 65 g ) wereadded to a stainless-steel pot (8.5cm i.d., 8.3 cm depth) containing twocounter-opposing lifting vanes to lift the seed as the pot turns. Thepot was oriented at a 40 to 45° angle from horizontal and mechanicallyrotated at 110 rpm, which gave good mixing and tumbling action insidethe pot.

[0295] The 6 flowables prepared in Step 1 were each sprayed directly ona tumbling bed of corn seed following the general procedure described inExample E, Step 2. The drying of the seed coating was then completed byallowing seeds to dry overnight in a chemical fume hood Nominal 3% byweight coatings of each micronized compound on corn seed were achievedas shown in Table 11. TABLE 11 Measurements for Corn Seed Coated withSeparate Compound Compositions Compound Compound Compound CompoundCompound Compound Measurement 208 484 486 509 502 515 Weight of CornSeed   65 g   65 g 65.15 g   65 g 65.04 g 64.02 g Batch Weight offlowable 15.28 g 14.46 g 15.49 g 15.25 g 15.25 g 15.31 g suspensionsprayed on seed % of flowable suspension 91.82% 88.62% 95.74% 92.96%92.82% 91.78% delivered on seed Weight of treated seed 68.03 g 67.88 g68.48 g 68.31 g 68.66 g 67.93 g batch after drying Average weight of 2.1 mg  1.92 mg  2.21 mg  2.13 mg  2.12 mg  2.11 mg compounds per seed*Average weight % of  3.14%  2.87%  3.28%  3.17%  3.16%  3.19% compoundson coated seed*

EXAMPLE G Preparation of Cottonseed Batches Coated With CompositionsComprising Compounds 208, 276 or 483 Step 1: Preparation of 3 FlowableSuspensions Comprising Compounds 208, 276 or 483

[0296] Three flowable suspensions, each containing one of the threecompounds above, were prepared using the same recipe as shown in Table 9of Example F. A flowable suspension of each compound was prepared by themethod as described in Example E, Step 1. The diameters (i.e. Dia. inTable 10) of the particles in the suspension were analyzed by the methodalso described in Example E, Step 1. The particle diameter distributionachieved after wet milling are shown in Table 12. TABLE 12 ParticleSizes of the 3 Flowable Suspensions Compound Compound Compound 483 502276 Mean Particle Dia. =*  1.5 μm 1.01 μm 1.17 μm 90% of Particle Dia.<* 3.23 μm 2.23 μm 2.37 μm Median Particle Dia. 1.11 μm 0.69 μm 0.92 μm10% of Particle Dia. <* 0.33 μm 0.28 μm  0.3 μm

Step 2: Coating Cottonseed With Separate Compositions ComprisingCompounds 208, 276 or 483

[0297] Cottonseed (Stoneville 4793 RR, 33 g ) were added to astainless-steel pot (6.5 cm i.d., 7.5 cm depth) containing twocounter-opposing lifting vanes to lift the seed as the pot turns. Thepot was oriented at a 40 to 45° angle from horizontal and mechanicallyrotated at 100 rpm, gave good mixing and tumbling action inside the pot.

[0298] The 3 flowables prepared in Step 1, were sprayed directly onseparate batches of tumbling cottonseed following the general proceduredescribed in Example E, Step 2. The drying of the seed coating was thencompleted by allowing seeds to dry overnight in a chemical fume hood.Nominal 3% by weight coatings of each micronized compound on cottonseedwere achieved as shown in Table 13. TABLE 13 Measurements for CottonseedCoated with Separate Compound Compositions Compound Compound CompoundMeasurement 483 502 276 Weight of Cottonseed Batch 33 g 33 g 33 g Weightof flowable 7.35 g 7.31 g 7.25 g suspension sprayed on seed % offlowbale suspension 91.9% 95.77% 92.72% delivered on seed Weight oftreated seed batch 34.93 g 35.05 g 34.91 g after drying Average weightof compounds 1.01 mg 1.05 mg 1.01 mg per seed* Average weight % of  2.9%   3%  2.89% compounds on coated seed*

EXAMPLE H Preparation of Cornseed Batches Coated With CompositionComprising cCompound 502 Step 1: Preparation of Flowable SuspensionComprising 15% w/w Compound 502

[0299] A 15% flowable suspension of Compound 502 containing the sameingredients other than the compounds listed in Table 9, Example F wasprepared. The flowable suspension of compound 502 was prepared by themethod as described in Example E, Step 1. The diameters (i.e. Dia inTable 10) of the particles in the suspension were analyzed by the methodalso described in Example E, Step 1. The resultant particle diameterdistribution achieved after wet milling is shown in Table 14. TABLE 14Particle Sizes of the Flowable Suspension Compound 502 Mean ParticleDia. =* 0.89 μm 90% of Particle Dia. <* 1.96 μm Median Particle Dia.0.58 μm 10% of Particle Dia. <* 0.27 μm

Step 2: Coating Corn Seed With Composition Comprising Compound 502

[0300] Corn (maize) seed (Pioneer 34M94 Hybrid Field Corn, 575 g) wereadded to a stainless-steel pot (17 cm i.d., 16 cm depth) containing twocounter-opposing lifting vanes to lift the seed as the pot turns. Thepot was oriented at a 40 to 45° angle from horizontal and mechanicallyrotated at 200 rpm, giving good mixing and tumbling action inside thepot.

[0301] The 15% w/w flowable prepared in Step 1, was sprayed directly onseparate batches of tumbling corn seed following the general proceduredescribed in Example E, Step 2. The drying of the seed coating was thencompleted by allowing seeds to dry overnight in a chemical fume hood.Nominal 0.15, 0.29, 0.58, 1.09, 1.75% by weight coatings of micronizedCompound 502 on cornseed were achieved as shown in Table 15. The averageWt. % of Compound 502 on coated seed was measured by LC/MS following themethod in Step 2 of Example E. TABLE 15 Measurements for CottonseedCoated with Compound 502 Composition Nominal Nominal Nominal NominalNominal Measurement 1.75% batch 1.09% batch 0.58% batch 0.29% batch0.15% batch Weight of Cornseed Batch   575 g   575 g 575.22 g 575.28 g  575 g Weight of flowable  71.17 g  44.56 g  22.79 g  11.94 g  5.95 gsuspension sprayed on seed % of flowable suspension 96.11% 95.18% 97.38%93.42% 97.21% delivered on target Weight of treated seed batch 592.31 g577.92 g 572.15 g 578.12 g 576.74 g after drying Calculated weight of 10.26 g  6.36 g  3.33 g  1.67 g  0.87 g compound delivered on seedNominal Wt. % Seed Coating  1.75%  1.09%  0.58%  0.29%  0.15% AverageWt. % of Compound  1.35% —  0.42% —  0.13% 502 on coated seed*

[0302] The following Tests in the Biological Examples of the Inventiondemonstrate the efficacy of methods and compositions of the inventionfor protecting plants from specific arthropod pests. The pest controlprotection afforded by the compounds is not limited, however, to thesespecies. See Index Table A for compound descriptions. The followingabbreviations are used in the Index Table which follows: t is tertiary,n is normal, i is iso, s is secondary, c is cyclo, Me is methyl, Et isethyl, Pr is propyl and Bu is butyl; accordingly i-Pr is isopropyl, s-Buis secondary butyl, etc. The abbreviation “Ex.” stands for “Example” andis followed by a number indicating in which example the compound isprepared. INDEX TABLE A

R¹, R⁵, and R⁸ are H, except where indicated; B is O, except whereindicated. “CN” is bonded through carbon, not nitrogen; for example“CN—Ph” specifies cyanophenyl, not isocyanophenyl. Compound R³ R² R⁴, R⁵R⁶ R⁷ m.p. (° C.)  1 i-Pr H 2-Me CF₃ CH₃ 200-204  2(Ex. 1) i-Pr H 2-MeCF₃ Et 123-126  3 i-Pr H 2-Cl CF₃ CH₃ 233-235  4 t-Bu H 2-Me CF₃ Et215-218  5 i-Pr H 2-Me CH₃ Ph 238-239  6 i-Pr H 2-Me CH₃ CH₃ 206-208  7i-Pr H 2-Me CH₃ CH₂CF₃ 246-248  8 i-Pr H 2-Cl Et CF₃ 235-237  9 i-Pr H2-Me CH₃ CH₃, R⁸ is Cl 205-207  10 i-Pr H 2-Me CH₃ 4-CF₃—Ph 256-258  11i-Pr H 2-Me CH₃ 2-CF₃—Ph 204-206  12 t-Bu H 2-Me CH₃ Ph 236-238  13 i-PrH 2-F CH₃ Ph 227-229  14 i-Pr H 5-F CH₃ Ph 209-211  15 i-Pr H 2-Cl CH₃Ph 233-234  16 i-Pr H H CH₃ Ph 215-217  17 i-Pr H 2-NO₂ CH₃ Ph 236-237 18 i-Pr H 2-Cl CF₃ Ph 240-242  19(Ex. 2) i-Pr H 2-Me CF₃ Ph 260-262  20i-Pr H 2-I CH₃ Ph 250-251  21 i-Pr H 2-I CH₃ 2-CF₃—Ph 251-253  22 H H2-Me CH₃ Ph 253-255  23 Et Et 2-Me CH₃ Ph 182-184  24 t-Bu H 2-Cl CF₃ Ph232-234  25 i-Pr H 2-I CF₃ Ph 271-273  26 t-Bu H 2-I CF₃ Ph 249-250  27i-Pr H 2-Me CF₃ t-Bu 210-211  28 i-Pr H 2-Br CF₃ Ph 257-259  29 i-Pr H2-Br CH₃ Ph 246-247  30 i-Pr H 2-Me CF₃ 2-pyridinyl 237-238  31 i-Pr H2,5-di-Cl CF₃ Ph >250  32 B is S, i-Pr H 2-Me CF₃ Ph 169-172  33 i-Pr H2-Me CF₃ 2-Cl—Ph 208-209  34 i-Pr H 2-Cl CF₃ 2-Cl—Ph 234-235  35 i-Pr H2-Me CF₃ 4-Cl—Ph 289-290  36 i-Pr H 2-Cl CF₃ 4-Cl—Ph 276-278  37 i-Pr H2-Cl CF₃ 2-pyridinyl 239-240  38 i-Pr H 2-Me CF₃ 2-pyrimidinyl 205-208 39 i-Pr H 2-Me CF₃ 2-(3-CH₃-pyridinyl) 183-187  40 i-Pr H 2-Me CF₂CF₃Ph 231-232  41 i-Pr H 2-Cl CF₂CF₃ Ph 206-207  42 t-Bu H 2-Cl CF₂CF₃ Ph212-213  43 i-Pr H 2-Br CF₂CF₃ Ph 219-222  44 i-Pr H 2-Me CF₃ 3-Cl—Ph278-280  45 i-Pr H 2-Cl CF₃ 3-Cl—Ph 272-273  46 i-Pr H 2-Me CF₃ 2-F—Ph217-218  47 i-Pr H 2-Cl CF₃ 2-F—Ph 220-221  48 i-Pr H 2-Me CF₃ 4-F—Ph269-270  49 i-Pr H 2-Cl CF₃ 4-F—Ph 279-280  50 i-Pr H 2-CF₃ CF₃ Ph247-249  51 i-Pr H 2-Cl CF₃ i-Pr 255-258  52 i-Pr H 2-Me CF₃ 3-F—Ph277-278  53 i-Pr H 2-Cl CF₃ 3-F—Ph 256-257  54 i-Pr H 2-Me CF₃ 2-CF₃—Ph215-216  55 i-Pr H 2-Cl CF₃ 2-CF₃—Ph 230-231  56 i-Pr H 2-Me CF₃ 2-Br—Ph207-208  57 i-Pr H 2-Cl CF₃ 2-Br—Ph 239-240  58 i-Pr H 2-OCH₃ CF₃ Ph215-216  59 i-Pr H 5-Cl CF₃ 2-(3-CH₃-pyridinyl) 224-225  60 i-Pr H 5-MeCF₃ 2-(3-Cl-pyridinyl) 179-181  61 s-Bu H 2-Cl CF₃ Ph >240  62 c-Pr H2-Cl CF₃ Ph >240  63 Et H 2-Cl CF₃ Ph >240  64 t-Bu H 2-CF₃ CF₃ Ph230-233  65 Et H 2-CF₃ CF₃ Ph 246-249  66 CH(CH₃)CH₂SCH₃ H 2-CF₃ CF₃ Ph215-217  67 CH(CH₃)CH₂OCH₃ H 2-CF₃ CF₃ Ph 220-223  68 i-Pr H 5-Cl CF₃2-(3-Cl-pyridinyl) 230-233  69 i-Pr H 5-Me CF₃ 2-thiazolyl 201-203  70i-Pr H 5-Me CF₃ 2-pyrazinyl 252-253  71 i-Pr H 5-Me CF₃ 4-pyridinyl224-228  72 i-Pr H 2-Me CF₃ i-Pr 236-243  73 i-Pr H 2-Me CF₃ 2-CH₃—Ph211-212  74 i-Pr H 2-Cl CF₃ 2-CH₃—Ph 232-234  75 i-Pr H 2-Br CF₃ 2-Cl—Ph247-248  76 t-Bu H 2-Me CF₃ 2-Cl—Ph 216-217  77(Ex. 3) i-Pr H 2-Me CF₃2-(3-CF₃-pyridinyl) 227-230  78 CH₂CH₂Cl H 2-Cl CF₃ Ph 237-242  79CH₂CH₂CH₂Cl H 2-Cl CF₃ Ph 233-239  80 CH(CH₃)CO₂CH₃ H 2-Cl CF₃ Ph221-222  81 CH(i-Pr)CO₂CH₃ H 2-Cl CF₃ Ph 212-213 (S configuration)  82i-Pr H 2-Me CF₃ 2,6-di-Cl—Ph 267-268  83 i-Pr H 2-Cl CF₃ 2,6-di-Cl—Ph286-287  84 i-Pr H 2-Me Br Ph 253-255  85 i-Pr H 2-Cl Br Ph 247-248  86i-Pr H 2-Me CF₃ t-Bu 205-210  87 i-Pr H 2-Me CF₃ CH₂Ph 235-237  88 i-PrH 2-Me CF₃ 2-(3-CH₃O-pyridinyl) 221-222  89 i-Pr H 2-Me CF₃ 3-pyridinyl260-261  90 i-Pr H 2-Me CF₃ 4-quinolinyl >260  91 i-Pr H 2-Me CN2-(3-Cl-pyridinyl) 203-204  92 i-Pr H 2-Me CF₃ 2,4-di-F—Ph 245-246  93i-Pr H 2-Cl CF₃ 2,4-di-F—Ph 252-253  94 i-Pr H 2-Me CF₃ 2-Et—Ph 207-209 95 i-Pr H 2-Cl CF₃ 2-Et—Ph 221-222  96 i-Pr H H CF₃ 2-Cl—Ph 206-207  97t-Bu H H CF₃ 2-Cl—Ph 197-198  98 CH(CH₃)CH₂OCH₃ H H CF₃ 2-Cl—Ph 145-148 99 CH(CH₃)CH₂SCH₃ H H CF₃ 2-Cl—Ph 158-160 100 CH(CH₃)CH₂SCH₃ H 2-Cl CF₃Ph 184-186 101 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃ Ph 217-218 102 n-Pr H 2-Cl CF₃Ph 247-248 103 t-Bu H 2-Cl CF₃ Ph 244-245 104 CH₃ H 2-Cl CF₃ Ph >250 105i-Pr Me 2-Cl CF₃ Ph 193-194 106 CH₂C≡CH H 2-Cl CF₃ Ph >250 107 CH₂CH═CH₂H 2-Cl CF₃ Ph 248-249 108 CH₂(2-furanyl) H 2-Cl CF₃ Ph 246-247 109 i-PrH 2-Me CF₃ 4-(3,5-di-Cl-pyridinyl) 239-242 110 i-Pr H 2-Cl CF₃4-(3,5-di-Cl-pyridinyl) 229-231 111 CH(CH₃)CH₂SCH₃ H 2-Me CF₃ 2-Cl—Ph194-195 112 CH(CH₃)CH₂OCH₃ H 2-Me CF₃ 2-Cl—Ph 181-183 113 s-Bu H 2-MeCF₃ 2-Cl—Ph 199-200 114 c-Pr H 2-Me CF₃ 2-Cl—Ph 234-235 115 n-Pr H 2-MeCF₃ 2-Cl—Ph 222-223 116 t-Bu H 2-Me CF₃ 2-Cl—Ph 235-237 117 Me H 2-MeCF₃ 2-Cl—Ph 242-243 118 i-Pr Me 2-Me CF₃ 2-Cl—Ph 90-93 119 CH₂C≡CH H2-Me CF₃ 2-Cl—Ph 215-216 120 Et H 2-Me CF₃ 2-Cl—Ph 228-229 121 CH₂CH═CH₂H 2-Me CF₃ 2-Cl—Ph 227-228 122 CH₂(2-furanyl) H 2-Me CF₃ 2-Cl—Ph 218-219123 CH(CH₃)CH₂SCH₃ H 2-Me CF₃ Ph 179-180 124 CH(CH₃)CH₂OCH₃ H 2-Me CF₃Ph 219-220 125 s-Bu H 2-Me CF₃ Ph 244-245 126 c-Pr H 2-Me CF₃ Ph >250127 n-Pr H 2-Me CF₃ Ph 238-239 128 t-Bu H 2-Me CF₃ Ph 237-238 129 Me H2-Me CF₃ Ph 263-265 130 i-Pr Me 2-Me CF₃ Ph 178-179 131 CH₂CH≡CH₂ H 2-MeCF₃ Ph 253-254 132 Et H 2-Me CF₃ Ph 244-245 133 CH₂CH═CH₂ H 2-Me CF₃ Ph240-241 134 CH₂(2-furanyl) H 2-Me CF₃ Ph 245-246 135 i-Pr H 2-OCHF₂ CF₃2-Cl—Ph 200-201 136 i-Pr H 2-OCH₃ CF₃ 2-Cl—Ph 206-207 137 i-Pr H 2-I CF₃2-Cl—Ph 253-256 138 i-Pr H 2-Me Br 2-Cl—Ph 147-150 139 i-Pr H 2-Cl Br2-Cl—Ph 246-247 140 i-Pr H 2-Me CF₃ 2-CH₃O—Ph 218-219 141 i-Pr H 2-ClCF₃ 2-CH₃O—Ph 243-244 142 i-Pr H 2-Me CF₃ 1-isoquinolinyl 252-253 143CH(CH₃)CH₂SCH₃ H 2-Cl CF₃ 2-Cl—Ph 217-218 144 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃2-Cl—Ph 207-208 145 s-Bu H 2-Cl CF₃ 2-Cl—Ph 216-217 146 c-Pr H 2-Cl CF₃2-Cl—Ph 261-262 147 n-Pr H 2-Cl CF₃ 2-Cl—Ph 231-232 148 t-Bu H 2-Cl CF₃2-Cl—Ph 255-256 149 Me H 2-Cl CF₃ 2-Cl—Ph 233-235 150 i-Pr Me 2-Cl CF₃2-Cl—Ph 127-128 151 CH₂C≡CH H 2-Cl CF₃ 2-Cl—Ph 226-227 152 Et H 2-Cl CF₃2-Cl—Ph 244-246 153 CH₂CH═CH₂ H 2-Cl CF₃ 2-Cl—Ph 235-236 154CH₂(2-furanyl) H 2-Cl CF₃ 2-Cl—Ph 207-208 155 i-Pr H C≡CH CF₃ 2-Cl—Ph228-230 156 i-Pr H 2-Cl C≡CH 2-Cl—Ph 219-222 157 i-Pr H 2-Me H H, R⁸ isCH₃ 220-223 158 i-Pr H 2-Me CH₃ Ph, R⁸ is Cl 209-210 159 B is S, i-Pr H2-Cl CF₃ Ph 169-174 160 i-Pr H 2-Me CF₃ 2,6-di-F—Ph 223-225 161 i-Pr H2-Me CF₃ 2-Cl-6-F—Ph 203-206 162 i-Pr H 2-Cl CF₃ 2-Cl-6-F—Ph 218-221 163i-Pr H 2-Me-4-Br CF₃ 2-F—Ph 232-233 164 t-Bu H 2-Cl CF₃2-(3-Cl-pyridinyl) 250-251 165

H 2-Cl CF₃ 2-(3-Cl-pyridinyl) >250 166 Et Et 2-Cl CF₃ 2-Cl—Ph 243-247167 Me Me 2-Cl CF₃ 2-Cl—Ph 234-235 168 Et Et 2-Me CF₃ 2-Cl—Ph 237-238169 Me Me 2-Me CF₃ 2-Cl—Ph 225-226 170 i-Pr H 2-Cl CF₃ 2-pyrazinyl242-243 171 t-Bu H 2-Me-4-Br CF₃ 2-Cl—Ph >260 172 CH(CH₃)CH₂OCH₃ H 2-MeCF₃ 2-(3-Cl-pyridinyl) 176-177 173 CH(CH₃)CH₂SCH₃ H 2-Me CF₃2-(3-Cl-pyridinyl) 196-197 174 CH(CH₃)CH₂OCH₃ H 2-Cl CF₃2-(3-Cl-pyridinyl) 197-198 175 CH(CH₃)CH₂SCH₃ H 2-Cl CF₃2-(3-Cl-pyridinyl) 202-203 176 i-Pr H 2-Me CF₃ 2-I—Ph 221-222 177 i-Pr H2-Cl CF₃ 2-I—Ph 238-240 178 i-Pr H 2-Me CF₃ 2-(HC≡C)—Ph 215-217 179 i-PrH 2-Cl CF₃ 2-(HC≡C)—Ph 244-246 180 i-Pr H 2-Me CF₃ 2-Cl-4-F—Ph 203-205181 i-Pr H 2-Cl CF₃ 2-Cl-4-F—Ph 218-219 182 Et Et 2-Me CF₃ 2-Cl—Ph243-247 183 i-Pr H 2-Me CF₃ 2,6-di-Me—Ph 259-260 184 i-Pr H 2-Cl CF₃2,6-di-Me—Ph 268-269 185 i-Pr H 2-Me CF₃ 2,6-di-Cl-4-CN—Ph * 186 i-Pr H2-Me CF₃ 2-CN—Ph 225-235 187 i-Pr H 2-Me CF₃ 2-(CF₃O)—Ph 214-215 188i-Pr H 2-Cl CF₃ 2-(CF₃O)—Ph 223-224 189 i-Pr H 2-Me CF₃ 2-Br-4-F—Ph202-203 190 i-Pr H 2-Cl CF₃ 2-Br-4-F—Ph 222-223 191 i-Pr H 2-Me CF₃2-(3-Me-pyrazinyl) 205-207 192 Me H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-220193 CH₂C≡CH H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 197-198 194 Me H 2-Me CF₃2-(3-Cl-pyridinyl) 193-196 195 Et H 2-Me CF₃ 2-(3-Cl-pyridinyl) 204-206196 CH₂C≡CH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 177-178 197 i-Pr H 2-Me CF₃4-(8-Cl-quinolinyl) >250 198 i-Pr H 2-Me CF₃ 4-(2-Me-quinolinyl) >250199 i-Pr H 2-Cl CF₃ 4-(2-Me-quinolinyl) >250 200 i-Pr H 2-Me CF₃4-(7-Cl-quinolinyl) >250 201 i-Pr H 2,4-Br₂ CF₃ 2-Cl—Ph 233-234 202 i-PrH 2-Br Br 2-Cl—Ph 255-258 203 Me H 2-Me Br 2-Cl—Ph 236-237 204 t-Bu H2-Cl Br 2-Cl—Ph 260-261 205 Et H 2-Me Br 2-Cl—Ph 254-255 206 t-Bu H 2-MeBr 2-Cl—Ph 259-260 207 c-Bu H 2-Cl CN 2-(3-Cl-pyridinyl) 177-180 208(Ex.4, 5) i-Pr H 2-Me CF₃ 2-(3-Cl-pyridinyl) 237-239 209 i-Pr H 2-Me CF₃4-(6-Cl-quinolinyl) >250 210 Me Me 2-Me CF₃ 4-(6-Cl-quinolinyl) >250 211i-Pr H 2-Cl CN 2-(3-Cl-pyridinyl) 195-200 212 t-Bu H 2-Cl CN2-(3-Cl-pyridinyl) >250 213 Et H 2-Cl CN 2-(3-Cl-pyridinyl) 200-205 214i-Pr H 2-Cl CF₃ 2-(3-Me-pyrazinyl) 225-230 215 t-Bu H 2-Cl CF₃2-(3-Me-pyrazinyl) 235-240 216 Et H 2-Cl CF₃ 2-(3-Me-pyrazinyl) 210-220217 i-Pr H 2-Me CF₃ 3-(2-Cl-pyridinyl) * 218 i-Pr H 2-Cl CF₃2,3-di-Cl—Ph 217-219 219 t-Bu H 2-Cl CF₃ 2,3-di-Cl—Ph 254-256 220 i-Pr H2-Me CF₃ 2,3-di-Cl—Ph 208-209 221 t-Bu H 2-Me CF₃ 2,3-di-Cl—Ph 232-233222 t-Bu H 2-Me-4-Br Br 2-Cl—Ph 239-241 223 Me H 2-Me-4-Br Br 2-Cl—Ph150-152 224 Et H 2-Me-4-Br Br 2-Cl—Ph 223-225 225 i-Pr H 2-Me-4-Br Br2-Cl—Ph 197-198 226 Me H 2-Me CF₃ 2-F—Ph 245-247 227 CH₂C≡CH H 2-Me CF₃2-F—Ph 222-227 228 Me Me 2-Cl CF₃ 2-Cl—Ph 234-236 229 CH₂C≡CH H2-Me-4-Br Br 2-Cl—Ph 187-188 230 i-Pr H 2-Cl CF₃ 2-(3-Me-pyridinyl)224-225 231 i-Pr H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 230-233 232 i-Pr H 2-MeCF₃ 2-pyrazinyl 252-253 233 i-Pr H 2-Me CF₃ 2-thiazolyl 201-203 234 i-PrH 2-Me CF₃ 4-pyridinyl 224-228 235 i-Pr H 2-Me CF₃ 2-(3-Cl-pyridinyl)249-250 236 i-Pr H 2-Me CF₃ Ph, R⁸ is CH₃ 246-248 237 Me Me 2-Me CF₃2-Cl—Ph 234-235 238 i-Pr H 2-Me CF₃ CH═CHCH₃ 225-228 239 i-Pr H 2-Me CF₃2-Cl-6-Me—Ph 240 i-Pr H 2-Cl CF₃ 2-Cl-6-Me—Ph 241 i-Pr H 2-Cl CF₃4-CN—Ph * 242 i-Pr H 2-Cl CF₃ 2,6-di-Cl-4-CN—Ph * 243 i-Pr H 2-Cl CF₃2-Cl-4-CN—Ph * 244 i-Pr H 2-Cl CN Ph * 245 i-Pr H 2-Me CF₃ 4-CN—Ph271-272 246 i-Pr H 2-Me CF₃ 3-CN—Ph 263-264 247 i-Pr H 2-Me CF₃2-Cl-4-CN—Ph * 248 i-Pr H 2-Me CN Ph * 249 i-Pr H 2-Cl CF₃ 3-CN—Ph * 250i-Pr H 2-Me CF₃ 2-Me-4-F—Ph 204-206 251 i-Pr H 2-Cl CF₃ 2-Me-4-F—Ph212-213 252 i-Pr H 2-Me CF₃ 2,4-di-Me—Ph 189-190 253 t-Bu H 2-Me CF₃2,4-di-Me—Ph 197-198 254 t-Bu H 2-Cl CF₃ 2,4-di-Me—Ph 234-235 255 i-Pr H2-Me CF₃ n-Bu, R⁸ is Cl 95-98 256 Me H 2-Cl CF₃ 4-(7-Cl-quinolinyl) >250257 Et H 2-Cl CF₃ 4-(7-Cl-quinolinyl) >250 258 CH₂CH═CH₂ H 2-Cl CF₃4-(7-Cl-quinolinyl) >250 259 i-Pr H 2-Cl CF₃ 4-(8-Cl-quinolinyl) >250260 i-Pr H 2-Me CF₃ 2-(3-CN-pyridinyl) 237-239 261 i-Pr H 2-Me CF₃1-(6-Cl-isoquinolinyl) >250 262 t-Bu H 2-Me CF₃ 1-(6-Cl-isoquinolinyl)227-229 263 Me Me 2-Me CF₃ 1-(6-Cl-isoquinolinyl) >250 264 i-Pr H 2-MeCF₃ 2-Cl-4-CN-6-Me—Ph * 265 i-Pr H 2-Me-4-Br Br 2-Cl—Ph 187-188 266CH₂CH(OCH₃)₂ H 2-Me CF₃ 2-Cl—Ph 205-207 267 CH₂CH(OCH₃)₂ Me 2-Me CF₃2-Cl—Ph 185-190 268 CH₂CH₂CH(OCH₃)₂ H 2-Me CF₃ 2-Cl—Ph 85-90 269 Me H2-Me CF₃ 2,6-di-Cl—Ph 280-282 270 Et H 2-Me CF₃ 2,6-di-Cl—Ph 274-275 271t-Bu H 2-Me CF₃ 2,6-di-Cl—Ph 285-286 272 t-Bu H 2-Cl CF₃ 2,6-di-Cl—Ph290-291 273 i-Pr H 2-Me H 2-Cl—Ph * 274 i-Pr H 2-Me H 2-Me—Ph * 275 i-PrH 2-Me H 2-F—Ph * 276 i-Pr H 2-Me Br 2-(3-Cl-pyridinyl) 206-209 277CH₂CH₂CN H 2-Me CF₃ 2-Cl—Ph 189-195 278 i-Pr H 2-Me CN 2-Cl—Ph * 279i-Pr H 2-Me CF₃ 2-(3-CH₃O-pyrazinyl) 195-200 280 i-Pr H 2-Me Br2,6-di-Cl—Ph 265-267 281 t-Bu H 2-Me Br 2,6-di-Cl—Ph 282-284 282 i-Pr H2-Cl Br 2,6-di-Cl—Ph 277-279 283 t-Bu H 2-Cl Br 2,6-di-Cl—Ph 296-298 284i-Pr H 2-Me Br 2-Cl-4-F—Ph 236-238 285 t-Bu H 2-Me Br 2-Cl-4-F—Ph249-250 286 i-Pr H 2-Cl Br 2-Cl-4-F 176-177 287 t-Bu H 2-Cl Br2-Cl-4-F—Ph 257-258 288 i-Pr H 2-I Br 2-Cl-4-F 227-229 289 c-Bu H 2-ClCF₃ 2-(3-Cl-pyridinyl) 230-231 290 i-Pr H 2-Cl Br 2-(3-Cl-pyridinyl)231-234 291 t-Bu H 2-Cl Br 2-(3-Cl-pyridinyl) 245-248 292 Et H 2-Cl Br2-(3-Cl-pyridinyl) 219-222 293 Et H 2-Me Br 2-(3-Cl-pyridinyl) 217-220294 t-Bu H 2-Me Br 2-(3-Cl-pyridinyl) 237-240 295 CH₂CN H 2-Me Br2-(3-Cl-pyridinyl) 227-229 296 t-Bu H 2-Me CN 2-(3-Cl-pyridinyl) 215-225297 c-Bu H 2-Me CN 2-(3-Cl-pyridinyl) 105-115 298 c-Bu H 2-Me CF₃2-(3-Cl-pyridinyl) 187-190 299 c-pentyl H 2-Me CF₃ 2-(3-Cl-pyridinyl)190-195 300 s-Bu H 2-Me CF₃ 2-(3-Cl-pyridinyl) 170-180 301 c-pentyl H2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-222 302 s-Bu H 2-Cl CF₃2-(3-Cl-pyridinyl) 210-220 306 i-Pr H 2-Me Cl 2-(3-Cl-pyridinyl) 204-206307 t-Bu H 2-Me Cl 2-(3-Cl-pyridinyl) 210-213 308 t-Bu H 2-Cl Cl2-(3-Cl-pyridinyl) 237-239 309 i-Pr H 2-Cl Cl 2-(3-Cl-pyridinyl) 159-162310 CH(CH₃)₂CH₂CH₃ H 2-Me CN 2-(3-Cl-pyridinyl) 165-175 311 c-hexyl H2-Cl CF₃ 2-(3-Cl-pyridinyl) 250-260 312 CH(CH₃)₂CH₂CH₃ H 2-Cl CF₃2-(3-Cl-pyridinyl) 200-210 313 i-Pr H 2,4-di-Me CF₃ 2-Cl—Ph 239-240 314i-Pr H 2-Me CF₃ 2-Cl-5-CN—Ph * 315 i-Pr H 2-Me H 2-(3-Cl-pyridinyl)111-115 316 i-Pr H 2-Me CF₃ 2-CO₂Me—Ph 317 i-Pr H 2-Me-4-Br CF₃2,6-di-Cl—Ph 230-233 318 t-Bu H 2-Me-4-Br CF₃ 2,6-di-Cl—Ph >250 319 Me H2-Me-4-Br CF₃ 2,6-di-Cl—Ph 228-230 320 CH₂CN H 2-Me-4-Br CF₃2,6-di-Cl—Ph 228-230 321 i-Pr H 2,4-di-Cl CF₃ 2-Cl—Ph 223-224 322 i-Pr H2-Me CF₃ 2-Cl-4-CF₃-6-Cl—Ph 206-207 323 i-Pr H 2-Me CF₃5-(1,3-di-Me-4-Cl-pyrazolyl) 324 i-Pr H 2-Me CF₃2-(4,6-di-Me-pyrimidinyl) 220-222 325 i-Pr H 2-Cl CF₃2-(4,6-di-Me-pyrimidinyl) 152-154 326 t-Bu H 2-Me CF₃2-(4,6-di-Me-pyrimidinyl) 124-127 327 t-Bu H 2-Cl CF₃2-(4,6-di-Me-pyrimidinyl) 179-182 328 i-Pr H 4-I CF₃ 2-Cl—Ph 218-219 329i-Pr H 2-Me-4-OCH₃ CF₃ 2-(3-Cl-pyridinyl) 187-188 330 i-Pr H 2-Me CF₃2-F-4-Cl-5-(i-PrO)—Ph 214-216 331 CH₂CN H 2-Me Cl 2-(3-Cl-pyridinyl)190-195 332 Et H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 217-219 333 i-Pr H2-Me-4-Br CF₃ 2,3-di-Cl—Ph >250 334 i-Pr H 2-Me CF₃ 2,5-di-Cl—Ph >250335 i-Pr H 2-Cl-4-Br CF₃ 2,3-di-Cl—Ph 251-253 336 CH₂N H 2-Cl CF₃2,3-di-Cl—Ph 185-190 337 CH₂CH₂SCH₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl)197-200 338 CH₂CH₂CH₂SCH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 185-190 339CH₂(2-furanyl) H 2-Me CF₃ 2-(3-Cl-pyridinyl) 210-215 340 CH₂C(═CH₂)CH₃ H2-Me CF₃ 2-(3-Cl-pyridinyl) 225-229 341 CH₂CH₂OCH₃ H 2-Me CF₃2-(3-Cl-pyridinyl) 215-218 342 CH₂CH₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl)210-212 343 CH₂CH₂Cl H 2-Me CF₃ 2-(3-Cl-pyridinyl) 206-216 344 CH₂CH₂OHH 2-Me CF₃ 2-(3-Cl-pyridinyl) 217-220 345 CH(CH₃)CH₂OH H 2-Me CF₃2-(3-Cl-pyridinyl) 110-115 346 CH₂CH(Br)CH₂Br H 2-Me CF₃2-(3-Cl-pyridinyl) 217-220 347 CH₂CO₂CH₃ H 2-Me CF₃2-(3-Cl-pyridinyl) >250 348 CH₂CH(OH)CH₂OH H 2-Me CF₃2-(3-Cl-pyridinyl) >250 349 CH₂CH₂CH₂Cl H 2-Me CF₃ 2-(3-Cl-pyridinyl)207-212 350 CH(CH₂OH)CH₂CH₃ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 173-176 351i-Pr H 2-Me CF₃ 2-(5-CF₃-pyridinyl) 270-275 352 Et H 2-Me CF₃2-(3,6-di-Me-pyrazinyl) 210-215 353 i-Pr H 2-Me CF₃2-(3,6-di-Me-pyrazinyl) 215-220 354 t-Bu H 2-Me CF₃2-(3,6-di-Me-pyrazinyl) 265-270 355 Et H 2-Cl CF₃2-(3,6-di-Me-pyrazinyl) 214-217 356 i-Pr H 2-Cl CF₃2-(3,6-di-Me-pyrazinyl) 215-218 357 i-Pr H 2-Me OCH₃ 2-Cl—Ph 137-140 358i-Pr H 2-Cl OCH₃ 2-Cl—Ph 155-158 359 i-Pr H 2-Me Me 2-Cl—Ph 151-154 360i-Pr H 2-Cl Me 2,6-di-Cl—Ph 242-244 361 CH₂CH(OH)CH₃ H 2-Me CF₃2-(3-Cl-pyridinyl) 123-125 362 CH₂CH(OH)CH₂CH₃ H 2-Me CF₃2-(3-Cl-pyridinyl) 175-180 363 CH₂CN H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl)142-143 364 c-Pr H 2,4-di-Br CF₃ 2-(3-Cl-pyridinyl) 213-214 365 CH₂CN H2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 201-202 366 i-Pr H 2,6-di-Me CF₃2-(3-Cl-pyridinyl) 204-205 367 t-Bu H 2,6-di-Me CF₃ 2-(3-Cl-pyridinyl)242-243 368 t-Bu H 2-Me CF₃ 2-(5-CF₃-pyridinyl) 220-230 369 C(CH₃)₂CH₂OHH 2-Me CF₃ 2-(3-Cl-pyridinyl) 205-210 370 CH₂CH₂F H 2-Me CF₃2-(3-Cl-pyridinyl) 127-130 371 i-Pr H 2-Me CF₃ 2-(4-Me-pyrimidinyl)196-197 372 i-Pr H 2-Cl CF₃ 2-(4-Me-pyrimidinyl) 208-210 373 t-Bu H 2-MeCF₃ 2-(4-Me-pyrimidinyl) 180-182 374 t-Bu H 2-Cl CF₃2-(4-Me-pyrimidinyl) 182-184 375 s-Bu H 2-Me CF₃ 2-(3-Et-pyrazinyl)160-165 376 Et H 2-Me CF₃ 2-(3-Et-pyrazinyl) 185-190 377 i-Pr H 2-Me CF₃2-(3-Et-pyrazinyl) 180-183 378 CH₂CF₂CF₃ H 2-Cl CF₃ 2-Cl—Ph 258-260 379t-Bu H 2-Me CF₃ 2-(3-Et-pyrazinyl) 180-185 380 CH₂CF₃ H 2-Cl CF₃ 2-Cl—Ph262-264 381 CH₂CN H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 192-193 382CH(CH₃)CH₂OH H 2-Me CF3 2-Cl—Ph 203-205 383 i-Pr H 2-Me Cl 2-Cl—Ph207-209 384 i-Pr H 2-Cl Cl 2-Cl—Ph 236-237 385 i-Pr H 2-Me I 2-Cl—Ph225-226 386 i-Pr H 2-Cl I 2-Cl—Ph 251-253 387 CH(CH₃)CH₂Cl H 2-Me CF₃2-Cl—Ph 212-214 388 H H 2-Me CF₃ 2-(3-Cl-pyridinyl) 217-220 389 i-Pr H2-Cl CF₃ 4-(5,6-di-Me-pyrimidinyl) 218-220 390 t-Bu H 2-Cl CF₃4-(5,6-di-Me-pyrimidinyl) 212-214 391 i-Pr H 2-Cl CF₃4-(2,5,6-tri-Me-pyrimidinyl) 162-164 392 i-Pr H 2-Me CF₃4-(5,6-di-Me-pyrimidinyl) 162-164 393 CH₂CH(OH)CH₃ H 2-Me CF₃ 2-Cl—Ph207-209 394 H H 2-Me CF₃ 2-Cl—Ph 230-232 395 CH₂CH(Cl)CH₃ H 2-Me CF₃2-Cl—Ph 230-232 396 CH₂CH₂CN H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 215-217 397CH₂CH₂F H 2-Cl CF₃ 2-(3-Cl-pyridinyl) 212-214 398 CH₂CH₂CN H 2-Cl CF₃2-Cl—Ph * 399 i-Pr H 2-Me-4-Br CN 2-(3-Cl-pyridinyl) * 400 CH₂CN H2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 211-213 401 i-Pr H 2-Me CF₃2,5-di-F—Ph 179-181 402 i-Pr H 2,4-di-Br CN 2-(3-Cl-pyridinyl) * 403t-Bu H 2,4-di-Br CN 2-(3-Cl-pyridinyl) 145-147 404 Me H 2,4-di-Br CN2-(3-Cl-pyridinyl) 165-168 405 Et H 2,4-di-Br CN 2-(3-Cl-pyridinyl)179-181 406 Me H 2-Me-4-Br Me 2-(3-Cl-pyridinyl) 141-143 407 t-Bu H2-Me-4-Br Me 2-(3-Cl-pyridinyl) 161-163 408 i-Pr H 2-Me-4-Br Me2-(3-Cl-pyridinyl) 141-143 409 Et H 2-Me-4-Br Me 2-(3-CL-pyridinyl)161-163 410 i-Pr H 2-Me Me 2-(3-Cl-pyridinyl) 193-195 411 Me H 2-Me Me2-(3-Cl-pyridinyl) 194-196 412 i-Pr H 2-Me-4-Cl CN 2-(3-Cl-pyridinyl)188-190 413 t-Bu H 2-Me-4-Cl CN 2-(3-Cl-pyridinyl) 148-151 414 Me H2-Me-4-Cl CN 2-(3-Cl-pyridinyl) 182-184 415 Me H 2-Me Br2-(3-Cl-pyridinyl) 210-212 416 H H 2-Cl CF₃ 2-Cl—Ph 203-205 417 H H2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 243-245 418 t-Bu H 2-Me CF₃5-(1,3-di-Me-4-Cl-pyrazolyl) 419 i-Pr H 2-Cl CF₃5-(1,3-di-Me-4-Cl-pyrazolyl) 420 t-Bu H 2-Cl CF₃5-(1,3-di-Me-4-Cl-pyrazolyl) 421 CH₂CN H 2-Br-4-Me CF₃2-(3-Cl-pyridinyl) 149-150 422 i-Pr H 2-Me-4-Cl Cl 2-Cl—Ph 180-181 423i-Pr H 2-Me-4-Br Br 2,6-di-Cl—Ph 238-239 424 i-Pr H 2-Cl-4-Me CF₃2-(3-Cl-pyridinyl) 170-171 425 t-Bu H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl)167-169 426 Me H 2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 162-164 427 H H2-Me-4-Br Br 2-(3-Cl-pyridinyl) 235-237 428 Me H 5-Cl CF₃2-(3-Cl-pyridinyl) 207-208 429 CH₂CN H 5-Cl CF₃ 2-(3-Cl-pyridinyl)178-179 430 Me H 5-Me CF₃ 2-(3-Cl-pyridinyl) 166-167 431 CH₂CN H 5-MeCF₃ 2-(3-Cl-pyridinyl) 191-192 432 H H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl)243-244 433 i-Pr H 2-Me CF₃ 4-pyrimidinyl 434 i-Pr H 2-Cl CF₃4-pyrimidinyl 435 t-Bu H 2-Me CF₃ 4-pyrimidinyl 436 t-Bu H 2-Cl CF₃4-pyrimidinyl 437 i-Pr H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 173-175 438t-Bu H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl) 149-150 439 Me H 2,3-di-Me CF₃2-(3-Cl-pyridinyl) 164-166 440 H H 2,3-di-Me CF₃ 2-(3-Cl-pyridinyl)201-203 441 H H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 240-242 442 H H2-Cl-4-Me CF₃ 2-(3-Cl-pyridinyl) 223-225 443 i-Pr H 2-Me CF₃4-(5-Cl-pyrimidinyl) 444 t-Bu H 2-Me CF₃ 4-(5-Cl-pyrimidinyl) 445 t-Bu H2-Cl CF₃ 4-(5-Cl-pyrimidinyl) 446 c-Pr H 2-Cl CF₃ 2-(3-Cl-pyridinyl)224-228 447 CH₂CN H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 232-234 448 CH₂CN H2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 221-222 449 Me H 2,4-di-Cl CF₃ 2-Cl—Ph232-233 450 Et H 2,4-di-Cl CF₃ 2-Cl—Ph 247-248 451 t-Bu H 2,4-di-Cl CF₃2-Cl—Ph 223-224 452 CH₂CN H 2,4-di-Cl CF₃ 2-Cl—Ph 229-231 453 i-Pr H2-Me CF₃ 5-(1-Me-pyrazolyl) 454 t-Bu H 2-Me CF₃ 5-(1-Me-pyrazolyl) 455i-Pr H 2-Cl CF₃ 5-(1-Me-pyrazolyl) 456 t-Bu H 2-Cl CF₃5-(1-Me-pyrazolyl) 457 i-Pr H 2-Me CF₃ 4-(2,6-di-Me-5-Cl- pyrimidinyl)458 i-Pr H 2-Cl CF₃ 4-(2,6-di-Me-5-Cl- pyrimidinyl) 459 t-Bu H 2-Me CF₃4-(2,6-di-Me-5-Cl- pyrimidinyl) 460 t-Bu H 2-Cl CF₃ 4-(2,6-di-Me-5-Cl-pyrimidinyl) 461 Et H 2-Me Cl 2-(3-Cl-pyridinyl) 220-221 462 Me H 2-MeCl 2-(3-Cl-pyridinyl) 217-218 463 CH₂C≡CH H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 199-201 464 CH₂C≡CH H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl)219-221 465 H H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 231-233 466 H H2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 245-247 467 CH₂C≡CH H 2,4-di-Cl Cl2-(3-Cl-pyridinyl) 166-168 468 H H 2-Me Cl 2-(3-Cl-pyridinyl) 243-244469 H H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 241-242 470 CH₂CN H 2-Me-4-Cl Br2-(3-Cl-pyridinyl) 225-226 471 CH₂C≡CH H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl)218-220 472 H H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 224-225 473 H H2,4-di-Br Cl 2-(3-Cl-pyridinyl) 250-252 474 i-Pr H 2-Me-4-Cl CF₃2-(3-Me-pyridinyl) 228-229 475 Me H 2-Me-4-Cl CF₃ 2-(3-Me-pyridinyl)226-227 476 t-Bu H 2-Me CF₃ 5-(1-Me-4-Cl-pyrazolyl) 477 i-Pr H 2-Me CF₃5-(1-Me-4-Cl-pyrazolyl) 478 i-Pr H 2-Me-4- CF₃ 2-(3-Cl-pyridinyl)199-201 (HOCH₂) 479 CH₂C≡CH H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 200-202480 B is S, i-Pr H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 214-217 481 i-Pr H2-Me-4- CF₃ 2-(3-Cl-pyridinyl) 204-206 CO₂Me 482 i-Pr H 2-Me-4- CF₃2-(3-Cl-pyridinyl) 168-170 CONHMe 483 i-Pr H 2-Me-4-Br CF₃2-(3-Cl-pyridinyl) 197-198 484(Ex. 6) i-Pr H 2-Me-4-Cl CF₃2-(3-Cl-pyridinyl) 195-196 485 t-Bu H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl)223-225 486(Ex. 7) Me H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 185-186 487i-Pr H 2-Br-4-Br CF₃ 2-(3-Cl-pyridinyl) 192-193 488 t-Bu H 2-Br-4-Br CF₃2-(3-Cl-pyridinyl) 246-247 489 Me H 2-Br-4-Br CF₃ 2-(3-Cl-pyridinyl)162-163 490 Et H 2-Br-4-Br CF₃ 2-(3-Cl-pyridinyl) 188-189 491 i-Pr H2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 200-201 492 t-Bu H 2,4-di-Cl CF₃2-(3-Cl-pyridinyl) 170-172 493 Me H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl)155-157 494 Et H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 201-202 495 t-Bu H2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 247-248 496 Et H 2-Me-4-Br CF₃2-(3-Cl-pyridinyl) 192-193 497 i-Pr H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl)179-180 498 i-Pr H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 185-187 499 i-Pr H2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl) 235-236 500 Et H 2-Me-4-CF₃ CF₃2-(3-Cl-pyridinyl) 216-217 501 i-Pr H 2-Me-4-I CF₃ 2-(3-Cl-pyridinyl)188-189 502(Ex. 11) Me H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 162-164 503t-Bu H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 159-161 504 i-Pr H 2,4-di-Br Br2-(3-Cl-pyridinyl) 162-163 505 Me H 2,4-di-Br Br 2-(3-Cl-pyridinyl)166-168 506 t-Bu H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 210-212 507 i-Pr H2,4-di-Cl Br 2-(3-Cl-pyridinyl) 188-190 508 t-Bu H 2,4-di-Cl Br2-(3-Cl-pyridinyl) 179-180 509(Ex. 10) i-Pr H 2-Me-4-Cl Br2-(3-Cl-pyridinyl) 159-161 510 i-Pr H 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl)200-202 511 t-Bu H 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 143-145 512 Me H2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 171-173 513 Me H 2-Me-4-Br Br2-(3-Cl-pyridinyl) 147-149 514 Me H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl)222-223 515(Ex. 8) i-Pr H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 173-175516(Ex. 9) Me H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 225-226 517 t-Bu H2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 163-165 518 i-Pr H 2-Me-4-Br Cl2-(3-Cl-pyridinyl) 152-153 519 Me H 2-Me-4-Br Cl 2-(3-Cl-pyridinyl)140-141 520 t-Bu H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 215-221 521 Me H2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 199-200 522 t-Bu H 2-Me-4-CF₃ CF₃2-(3-Cl-pyridinyl) 148-149 523 Et H 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl)199-200 524 i-Pr H 2,4-di-Br Cl 2-(3-Cl-pyridinyl) 197-199 525 Me H2,4-di-Br Cl 2-(3-Cl-pyridinyl) 188-190 526 t-Bu H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 194-196 527 Et H 2,4-di-Br Cl 2-(3-Cl-pyridinyl)192-194 528 i-Pr H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 197-199 529 Me H2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 205-206 530 t-Bu H 2,4-di-Cl Cl2-(3-Cl-pyridinyl) 172-173 531 Et H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl)206-208 532 t-Bu H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 124-125 533 Et H2,4-di-Br Br 2-(3-Cl-pyridinyl) 196-197 534 Me H 2,4-di-Cl Br2-(3-Cl-pyridinyl) 245-246 535 Et H 2,4-di-Cl Br 2-(3-Cl-pyridinyl)214-215 536 Et H 2-Me-4-Br Br 2-(3-Cl-pyridinyl) 194-196 537 Me H2-Me-4-I Br 2-(3-Cl-pyridinyl) 229-230 538 i-Pr H 2-Me-4-I Br2-(3-Cl-pyridinyl) 191-192 539 Me H 2-Me-4-CF₃ CF₃ 2-(3-Cl-pyridinyl)249-250 540 Et H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 163-164 541 Et H2-Me-4-I CF₃ 2-(3-Cl-pyridinyl) 199-200 542 t-Bu H 2-Me-4-I CF₃2-(3-Cl-pyridinyl) 242-243 543 Et H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl)194-195 544 Me H 2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 213-214 545 Et H2-Me-4-F CF₃ 2-(3-Cl-pyridinyl) 212-213 546 t-Bu H 2-Me-4-F CF₃2-(3-Cl-pyridinyl) 142-143 547 Me H 2-Me-4-F Br 2-(3-Cl-pyridinyl)214-215 548 Et H 2-Me-4-F Br 2-(3-Cl-pyridinyl) 205-205 549 i-Pr H2-Me-4-F Br 2-(3-Cl-pyridinyl) 206-208 550 i-Pr H 2-Me-4-F Cl2-(3-Cl-pyridinyl) 184-185 551 Me H 2-Me-4-F Cl 2-(3-Cl-pyridinyl)180-182 552 Et H 2-Me-4-F Cl 2-(3-Cl-pyridinyl) 163-165 553 Et H2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 192-194 554 Me H 2-Me-4-I Cl2-(3-Cl-pyridinyl) 233-234 555 Et H 2-Me-4-I Cl 2-(3-Cl-pyridinyl)196-197 556 i-Pr H 2-Me-4-I Cl 2-(3-Cl-pyridinyl) 189-190 557 t-Bu H2-Me-4-I Cl 2-(3-Cl-pyridinyl) 228-229 558 CH(CH₃)Ph H H CF₃ Me 212-214559 CH(CH₃)Ph H H CF₃ Et 202-203 560 CH₂CH₂N(i-Pr) H 2-Me CF₃ 2-Cl—Ph188-190 561 CH₂(4-(2,2-di-Me- H 2-Me CF₃ 2-Cl—Ph 195-200[1,3]-dioxolanyl)) 562 i-Pr H 2-Me CF₃ 2-CH₂NHC(═O)CF₃—Ph 563 i-Pr H2-Me CF₃ 2-CH₂NH₂—Ph HCl * 564 i-Pr H 2-Me CF₃ 2,4-di-Cl-5-OCH₂C≡CH—Ph246-249 565 CH₂(2- H 2-Me CF₃ 2-(3-Cl-pyridinyl) 222-225tetrahydrofuranyl) 566 CH₂(2-oxiranyl) H 2-Me CF₃ 2-(3-Cl-pyridinyl)183-185 567 CH₂CH₂OCH₂CH₂OH H 2-Me CF₃ 2-(3-Cl-pyridinyl) 132-135 568OCH(CH₃)₂ H 2-Cl CF₃ 2-Cl—Ph 218-219 569 OCH(CH₃)₂ H 2-Cl CF₃2-(3-Cl-pyridinyl) 205-206 570 OCH(CH₃)₂ H 2-Me CF₃ 2-(3-Cl-pyridinyl)210-211 571 OCH(CH₃)₂ H 2-Me CF₃ 2-Cl—Ph 196-198 572 i-Pr H 2-Me CF₃2-CONHMe—Ph * 573 Me H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 208-210 574 i-PrH 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 127-128 575 t-Bu H 2-Br-4-Me CF₃2-(3-Cl-pyridinyl) 159-160 576 Et H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl)224-225 577 Me H 2-Br-4-Me CF₃ 2-(3-Cl-pyridinyl) 208-209 578 t-Bu H2-Me-4-Br Cl 2-(3-Cl-pyridinyl) 224-225 579 Me H 2-Me-4-Cl I2-(3-Cl-pyridinyl) 208-209 580 i-Pr H 2-Me-4-Cl I 2-(3-Cl-pyridinyl)183-184 581 H H 2-Me-4-Cl I 2-(3-Cl-pyridinyl) 228-230 582 Me H2-Me-4-Cl Br 2-Cl-4-F—Ph 250-251 583 H H 2-Me-4-Cl Br 2-Cl-4-F—Ph229-229 584 i-Pr H 2-Me-4-Cl Br 2-Cl-4-F—Ph 189-190 585 t-Bu H 2-Me-4-ClBr 2-Cl-4-F—Ph 247-249 586 i-Pr H 2-Me-4-NO₂ CF₃ 2-Cl—Ph * 587 Ph H2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 243-244 588 2-Me—Ph H 2-Me-4-Cl CF₃2-(3-Cl-pyridinyl) 249-251 589 i-Pr H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl)170-172 590 i-Pr H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 591 Me, B is S H2-Me CF₃ 2-Cl—Ph 164-167 592 i-Pr H 2-NO₂ CF₃ 2-Cl—Ph * 593 i-Pr H2-Me-4-Cl OCHF₂ 2-Cl—Ph 177-179 594 Me Me 2,4-di-Br Cl2-(3-Cl-pyridinyl) 151-152 595 CH(CH₃)CH₂OCH₃ H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 162-163 596 CH(CH₃)CH₂SCH₃ H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 174-175 597 CH(CH₃)CH₂OH H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 148-149 598 i-Pr, R1 is Me H 2-Me Br2-(3-Cl-pyridinyl) 223-225 599 i-Pr, R1 is Me H 2-Me Cl2-(3-Cl-pyridinyl) 223-225 600 i-Pr, R1 is Me H 2-Me CF₃2-(3-Cl-pyridinyl) 218-219 601 i-Pr, B is S H 2-Me-4-Cl Br2-(3-Cl-pyridinyl) 231-235 602 N(CH₃)₂ H 2,4-di-Br Cl 2-(3-Cl-pyridinyl)149-151 603 N═C(NH₂)₂ H 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) * 604 N(Me)₂ H2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 185-188 605 i-Pr H 2-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 221-222 606 t-Bu H 2-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 217-218 607 CH(CH₃)CH₂CO₂Et H 2,4-di-Br Cl2-(3-Cl-pyridinyl) 113-115 608 2-pyridinyl H 2-Me-4-Br CF₃2-(3-Cl-pyridinyl) 244-245 609 2-(3-Me-pyridinyl) H 2-Me-4-Br CF₃2-(3-Me-pyridinyl) 182-183 610 i-Pr H 2-Cl-4-NO₂ CF₃2-(1-Me-3-Cl-pyridinium⁺ * CF₃SO₃ ⁻) 611 i-Pr H 2-Me-4-NO₂ CF₃2-(1-Me-3-Cl-pyridinium⁺ * CF₃SO₃ ⁻) 612 Me, B is S H 2-Me-4-Cl Br2-(3-Cl-pyridinyl) 110-113 613 Me Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl)207-208 614 Et Et 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 189-190 6152-pyridinyl H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 233-234 6162-(3-Me-pyridinyl) H 2-Me-4-Cl CF₃ 2-(3-Cl-pyridinyl) 202-203 617 Et Et2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 197-198 618 Me Me 2,4-di-Cl Cl2-(3-Cl-pyridinyl) 142-143 619 CH(CH₃)CH₂SCH₃ H 2,4-di-Cl Cl2-(3-Cl-pyridinyl) 185-186 620 Et Et 2,4-di-Br Cl 2-(3-Cl-pyridinyl)209-210 621 i-Pr Me 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 133-135 622 Me Me2,4-di-Br Br 2-(3-Cl-pyridinyl) 185-187 623 Et Et 2,4-di-Br Br2-(3-Cl-pyridinyl) 204-205 624 CH(CH₃)CH₂SCH₃ H 2,4-di-Br Br2-(3-Cl-pyridinyl) 178-179 625 Et H 2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl)209-211 626 i-Pr H 2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl) 179-181 627 Me H2-Me-4-Br OCHF₂ 2-(3-Cl-pyridinyl) 190-192 628 Et H 2-Me-4-Cl OEt2-Cl—Ph 163-165 629 i-Pr H 2-Me-4-Cl OEt 2-Cl—Ph 173-175 630 Me H2-Me-4-Br OEt 2-Cl—Ph 155-158 631 Et Me 2,4-di-Br Br 2-(3-Cl-pyridinyl)181-183 632 Et Me 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 162-163 633 Et Me2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 174-175 634 Me Me 2,4-di-Cl Br2-(3-Cl-pyridinyl) 216-218 635 Et Et 2,4-di-Cl Br 2-(3-Cl-pyridinyl)190-191 636 CH(CH₃)CH₂SCH₃ H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 182-183 637Et Me 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 165-167 638 Et H 2-Me-4-NO₂ CF₃2-(3-Cl-pyridinyl) * 639 Me Me 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 640CH₂CH═CH₂ H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 641 n-Pr H 2-Me-4-NO₂CF₃ 2-(3-Cl-pyridinyl) * 642 CH(CH₃)CH₂SCH₃ H 2-Me-4-NO₂ CF₃2-(3-Cl-pyridinyl) * 643 Me H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 644t-Bu H 2-Me-4-NO₂ CF₃ 2-(3-Cl-pyridinyl) * 645 CH₂CH₂N(Me)₂ H 2-Me-4-NO₂CF₃ 2-(3-Cl-pyridinyl) 193-195 646 CH₂CH₂N(Me)₃ ⁺I⁻ H 2-Me-4-NO₂ CF₃2-(3-Cl-pyridinyl) >250 647 1-pyrrolidine H 2,4-di-Cl Cl2-(3-Cl-pyridinyl) 143-145 648 N(CH₃)₂ H 2,4-di-Cl Cl 2-(3-Cl-pyridinyl)146-148 649 N(CH₃)₂ H 2,4-di-Br Br 2-(3-Cl-pyridinyl) 162-164 650N(CH₃)₂ H 2,4-di-Cl Br 2-(3-Cl-pyridinyl) 208-209 651 Et H 2-Me-4-ClOCH₂CF₃ 2-Cl—Ph 184-186 652 i-Pr H 2-Me-4-Cl OCH₂CF₃ 2-Cl—Ph 196-198 653Me H 2-Me-4-Br OCH₂CF₃ 2-Cl—Ph 220-223 654 N(CH₃)₂ H 2-Me-4-NO2 CF₃2-(3-Cl-pyridinyl) * 655 H H 2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 240-242 656n-Pr n-Pr 2-Me-4-Br CF₃ 2-(3-Cl-pyridinyl) 201-202 657 n-Pr H 2-Me-4-BrCF₃ 2-(3-Cl-pyridinyl) 188-190 658 Et Et 2-Cl CF₃ 2-(3-Cl-pyridinyl)242-243 659 n-Pr n-Pr 2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 242-243 660 n-Pr H2,4-di-Cl Cl 2-(3-Cl-pyridinyl) 218-219 661 CH₂CO₂CH₂CH₃ Me 2-Me-4-BrCF₃ 2-(3-Cl-pyridinyl) 227-228 662 CH₂CO₂CH₂CH₃ Me 2,4-di-Cl Br2-(3-Cl-pyridinyl) 176-177 663 CH₂CO₂CH₂CH₃ Me 2,4-di-Br Cl2-(3-Cl-pyridinyl) 198-199 664 CH₂CO₂CH₃ H 2-Me-4-Br CF₃2-(3-Cl-pyridinyl) 141-142 665 N(CH₃)₂ H 2,4-di-Cl CF₃2-(3-Cl-pyridinyl) 136-137 666 Me Me 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl)225-227 667 Et Et 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 228-229 668CH₂CO₂CH₂CH₃ Me 2,4-di-Cl CF₃ 2-(3-Cl-pyridinyl) 219-220 669 Me H2-Me-4-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 239-241 670 i-Pr H 2-Me-4-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 239-241 671 i-Pr H 2-Me-4-Br OEt2-(3-Cl-pyridinyl) 208-211 672 Me H 2-Me-4-Br OEt 2-(3-Cl-pyridinyl)212-215 673 i-Pr H 2-Me-4-Cl OEt 2-(3-Cl-pyridinyl) 191-193 674 Et H2-Me-4-Cl OEt 2-(3-Cl-pyridinyl) 207-209 675 i-Pr H 2-Me-4-Br OCH₂CF₃2-(3-Cl-pyridinyl) 213-215 676 Me H 2-Me-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl)206-208 677 i-Pr H 2-Me-4-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 211-213 678 Et H2-Me-4-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 205-207 679(Ex. 12) Me H 2-Me-4-ClOCH₂CF₃ 2-(3-Cl-pyridinyl) 195-197 680 Et H 2-Me-4-Br OCH₂CF₃2-(3-Cl-pyridinyl) 208-211 681 t-Bu H 2-Me-4-Br OCH₂CF₃2-(3-Cl-pyridinyl) 213-216 682 i-Pr H 2-Me-4-Br CF₃5-(1-Me-4-Cl-pyrazolyl) 256-258 683 t-Bu H 2-Me-4-Br CF₃5-(1-Me-4-Cl-pyrazolyl) 254-256 684 Me Me 2,4-di-Br CF₃2-(3-Cl-pyridinyl) 228-229 685 i-Pr H 2-Me-4-Cl OCF₂CHF₂2-(3-Cl-pyridinyl) 189-192 686 Et H 2-Me-4-Cl OCF₂CHF₂2-(3-Cl-pyridinyl) 189-192 687 Me H 2-Me-4-Cl OCF₂CHF₂2-(3-Cl-pyridinyl) 162-165 688 i-Pr H 2-Me-4-Br OCF₂CHF₂2-(3-Cl-pyridinyl) 185-188 689 Et H 2-Me-4-Br OCF₂CHF₂2-(3-Cl-pyridinyl) 195-198 690 Me H 2-Me-4-Br OCF₂CHF₂2-(3-Cl-pyridinyl) 164-167 691 Me Me 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl)238-239 692 Et Me 2-Cl-4-Br CF₃ 2-(3-Cl-pyridinyl) 216-217 693 H H H CF₃2-(3-Cl-pyridinyl) 694 Et H 2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl)249-251 695 i-Pr H 2,4-di-Cl OCH₂CF3 2-(3-Cl-pyridinyl) 232-235 696 Me H2,4-di-Cl OCH₂CF₃ 2-(3-Cl-pyridinyl) 192-195 697 Me Me 2,4-di-Cl OCH₂CF₃2-(3-Cl-pyridinyl) 132-135 698 i-Pr H 2,4-di-Br OCH₂CF₃2-(3-Cl-pyridinyl) 225-227 699 Me H 2,4-di-Br OCH₂CF₃ 2-(3-Cl-pyridinyl)206-208 700 Me Me 2,4-di-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 175-177 701 Me H2-Cl-4-Br Br 2-(3-Cl-pyridinyl) 226-227 702 Me Me 2-Cl-4-Br Br2-(3-Cl-pyridinyl) 237-238 703 Me H 2-Cl-4-Br Cl 2-(3-Cl-pyridinyl)228-229 704 Me Me 2-Cl-4-Br Cl 2-(3-Cl-pyridinyl) 236-237 705CH₂C(Me)₂CH₂N(Me)₂ H 2-Me CF₃ 2-(3-Cl-pyridinyl) 197-200 706 Me H2-Me-4-Br CF₃ 5-(1-Me-4-Cl-pyrazolyl) 242-244 707 Et H 2-Me-4-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 252-254 708 t-Bu H 2-Me-4-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 259-260 709 i-Pr H 2,4-di-Cl OCBrF₂2-(3-Cl-pyridinyl) 220-222 710 Me H 2,4-di-Cl OCBrF₂ 2-(3-Cl-pyridinyl)188-191 711 Me Me 2,4-di-Cl OCBrF₂ 2-(3-Cl-pyridinyl) 203-205 712 Me H2-Me-4-Cl OCHF₂ 2-(3-Cl-pyridinyl) 210-212 713 i-Pr H 2-Me-4-Cl OCBrF₂2-(3-Cl-pyridinyl) 194-196 714 Me H 2-Me-4-Cl OCBrF₂ 2-(3-Cl-pyridinyl)181-183 715 Me H 3,4-di-F Cl 2-(3-Cl-pyridinyl) 202-203 716 Me Me3,4-di-F Cl 2-(3-Cl-pyridinyl) 251-252 717 Me Me 2-Me-4-F Cl2-(3-Cl-pyridinyl) 242-243 718 Me Me 2-Cl-4-F Br 2-(3-Cl-pyridinyl)245-246 719 Me H 2-Cl-4-F Br 2-(3-Cl-pyridinyl) 217-218 720 i-Pr H2-Cl-4-F Br 2-(3-Cl-pyridinyl) 168-169 721 Me Me 2-Cl-4-F Cl2-(3-Cl-pyridinyl) 239-240 722 Me H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl)248-249 723 i-Pr H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 169-170 724 Me Me2-Cl-4-F CF₃ 2-(3-Cl-pyridinyl) 215-216 725 Me H 2-Cl-4-F CF₃2-(3-Cl-pyridinyl) 219-220 726 Me Me 2-Br-4-F Br 2-(3-Cl-pyridinyl)235-236 727 Me H 2-Br-4-F Br 2-(3-Cl-pyridinyl) 238-239 728 i-Pr H2-Br-4-F Br 2-(3-Cl-pyridinyl) 236-237 729 Me Me 2-Br-4-F Cl2-(3-Cl-pyridinyl) 246-247 730 Me H 2-Br-4-F Cl 2-(3-Cl-pyridinyl)233-234 731 i-Pr H 2-Br-4-F Cl 2-(3-Cl-pyridinyl) 153-154 732 i-Pr H2-Me-4-Cl OCHMe₂ 2-(3-Cl-pyridinyl) 208-210 733 Me H 2-Me-4-Cl OCHMe₂2-(3-Cl-pyridinyl) 207-210 734 i-Pr H 2,4-di-Cl OCHMe₂2-(3-Cl-pyridinyl) 187-191 735 Me H 2,4-di-Cl OCHMe₂2-(3-Cl-pyridinyl) * 736 Me Me 2-Br-4-F CF₃ 2-(3-Cl-pyridinyl) 191-192737 Me H 2-Br-4-F CF₃ 2-(3-Cl-pyridinyl) 228-229 738 i-Pr H 2-Br-4-F CF₃2-(3-Cl-pyridinyl) 224-226 739 Me Me 2-Br-4-Cl Br 2-(3-Cl-pyridinyl)188-189 740 Me H 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 248-249 741 i-Pr H2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 252-253 742 Me Me 2-Br-4-Cl Cl2-(3-Cl-pyridinyl) 147-148 743 Me H 2-Br-4-Cl Cl 2-(3-Cl-pyridinyl)249-250 744 i-Pr H 2-Br-4-Cl Cl 2-(3-Cl-pyridinyl) 239-240 745 Me Me2-Br-4-Cl CF₃ 2-(3-Cl-pyridinyl) 200-201 746 Me H 2-Br-4-Cl CF₃2-(3-Cl-pyridinyl) 158-159 747 i-Pr H 2-Br-4-Cl CF₃ 2-(3-Cl-pyridinyl)250-250 748 Me Me 2-Me-4-Cl Cl 2-(3-Cl-pyridinyl) 232-233 749 Me H 2-CF₃CF₃ 2-(3-Cl-pyridinyl) 218-220 750 i-Pr H 2-CF₃ CF₃ 2-(3-Cl-pyridinyl)242-246 751 Me Me 2-CF₃ CF₃ 2-(3-Cl-pyridinyl) 239-244 752 Me Me2-Me-4-Cl Br 2-(3-Cl-pyridinyl) 210-211 753 Me Me 2,4-di-Me Cl2-(3-Cl-pyridinyl) 223-224 754 Me Me 2,4-di-Me Br 2-(3-Cl-pyridinyl)240-241 755 Me H 2-F Br 2-(3-Cl-pyridinyl) 215-216 756 i-Pr H 2-F Br2-(3-Cl-pyridinyl) 213-215 757 i-Pr H 2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl)254-256 758 Me Me 2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl) 229-231 759 Me H2-CF₃-4-Cl CF₃ 2-(3-Cl-pyridinyl) 235-237 760 Me H 2,4-di-Cl CF₃2-(3-Cl-pyridinyl), R⁸ is Cl 225-226 761 i-Pr H 2,4-di-Cl CF₃2-(3-Cl-pyridinyl), R⁸ is Cl 230-232 762 Me Me 2,4-di-Cl CF₃2-(3-Cl-pyridinyl), R⁸ is Cl 194-196 763 i-Pr H 2-Me-4-Cl CF₃3-isoxazolyl 255-257 764 Me H 2,4-di-F Br 2-(3-Cl-pyridinyl) 197-198 765Me Me 2,4-di-F Br 2-(3-Cl-pyridinyl) 218-222 766 Me H 2-F Cl2-(3-Cl-pyridinyl) 185-187 767 Me H 2-F-4-Cl Br 2-(3-Cl-pyridinyl)203-204 768 Me Me 2-F-4-Cl Br 2-(3-Cl-pyridinyl) 226-227 769 i-Pr H2-F-4-Cl Br 2-(3-Cl-pyridinyl) 207-208 770 Me H 2-F-4-Cl Cl2-(3-Cl-pyridinyl) 211-212 771 Me Me 2-F-4-Cl Cl 2-(3-Cl-pyridinyl)237-238 772 i-Pr H 2-Me-4-CN CF₃ 2-(3-Cl-pyridinyl) * 773 H H 2-F-4-ClCl 2-(3-Cl-pyridinyl) 116-117 774 Me H 2,4-di-F Cl 2-(3-Cl-pyridinyl)159-160 775 Me Me 2,4-di-F Cl 2-(3-Cl-pyridinyl) 225-226 776 i-Pr H2,4-di-F Cl 2-(3-Cl-pyridinyl) 201-202 777 H H 2,4-di-F Cl2-(3-Cl-pyridinyl) 128-129 778 Et H 2-Me-4-Cl CF₃ 5-(1-CH₂CF₃-pyrazolyl)172-174 779 Me H 2-Me-4-Cl CF₃ 5-(1-CH₂CF₃-pyrazolyl) 192-194 780 Me H2,4-di-Cl F 2-(3-Cl-pyridinyl) * 781 Me H 2-F OCH₂CF₃ 2-(3-Cl-pyridinyl)202-203 782 Me Me 2-F OCH₂CF₃ 2-(3-Cl-pyridinyl) 178-179 783 i-Pr H 2-FOCH₂CF₃ 2-(3-Cl-pyridinyl) 161-162 784 Me H 2-F-4-Br Br2-(3-Cl-pyridinyl) 209-210 785 Me Me 2-F-4-Br Br 2-(3-Cl-pyridinyl)225-226 786 i-Pr H 2-F-4-Br Br 2-(3-Cl-pyridinyl) 208-209 787 Me H2-F-4-Br Cl 2-(3-Cl-pyridinyl) 209-210 788 Me Me 2-F-4-Br Cl2-(3-Cl-pyridinyl) 244-245 789 Me Me 2-F-4-Br Cl 2-(3-Cl-pyridinyl)207-208 790 Me H 2-F-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 210-211 791 Me Me2-F-4-Br OCH₂CF₃ 2-(3-Cl-pyridinyl) 204-206 792 i-Pr H 2,4-di-Cl CF₃3-(4-Cl-5-Me-isoxazolyl) 204-205 793 Me H 2,4-di-Cl CF₃3-(4-Cl-5-Me-isoxazolyl) 131-132 794 i-Pr H 2-Me-4-Cl CF₃3-(4-Cl-5-Me-isoxazolyl) 188-189 795 Me H 2-Me-4-Cl CF₃3-(4-Cl-5-Me-isoxazolyl) 210-211 796 i-Pr H 2,4-di-Cl CF₃3-(4-Cl-isoxazolyl) 212-213 797 i-Pr H 2-Me-4-Cl CF₃ 3-(4-Cl-isoxazolyl)232 798 Me H 2-Me-4-Cl CF₃ 3-(4-Cl-isoxazolyl) 190-191 799 Me H2,4-di-Cl CF₃ 3-(4-Cl-isoxazolyl) 209-210 800 i-Pr H 4-Cl CF₃3-(4-Cl-isoxazolyl) 241-242 801 i-Pr H 2,4-di-Cl CF₃5-(1-CH₂CF₃-pyrazolyl) 212-214 802 H H 2,4-di-Cl F 2-(3-Cl-pyridinyl) *803 i-Pr H 2,4-di-Cl F 2-(3-Cl-pyridinyl) * 804 Me Me 2,4-di-Cl F2-(3-Cl-pyridinyl) * 805 H H 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 806 i-Pr H2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 807 Me H 2-Me-4-Cl F2-(3-Cl-pyridinyl) * 808 Me Me 2-Me-4-Cl F 2-(3-Cl-pyridinyl) * 809 Me H2,4-di-Cl CF₃ 5-(1-Me-4-Cl-pyrazolyl) 242-244 810 Et H 2,4-di-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 266-268 811 i-Pr H 2,4-di-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 241-243 812 Me Me 2,4-di-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 202-204 813 t-Bu H 2,4-di-Cl CF₃5-(1-Me-4-Cl-pyrazolyl) 128-131 814 Me H 2,4-di-Cl CF₃2-(3-Cl-pyridinyl) * 815 H H 2-F-4-Br Br 2-(3-Cl-pyridinyl) 151-152 816H H 2-Cl-4-F Cl 2-(3-Cl-pyridinyl) 133-134 817 Me H 2,4-di-F F2-(3-Cl-pyridinyl) 166-167 818 H H 2-F-4-Br Cl 2-(3-Cl-pyridinyl)148-149 819 H H 2-Br-4-Cl Br 2-(3-Cl-pyridinyl) 134-136 820 Me Me2,4-di-F F 2-(3-Cl-pyridinyl) 211-212 821 H H 2,4-di-F F2-(3-Cl-pyridinyl) 115-117 822 i-Pr H 2,4-di-F F 2-(3-Cl-pyridinyl)157-158 823 i-Pr H 2-Cl-4-I Cl 2-(3-Cl-pyridinyl) 192-195 824 i-Pr H2,4-di-Cl OCH₃ 2-(3-Cl-pyridinyl) 191-194 825 Me H 2,4-di-Cl OCH₃2-(3-Cl-pyridinyl) 143-145 826 Me H 2-Me-4-Cl Br 2-(3-Cl-5-Br-pyridinyl)216-219 827 Me H 2-F F 2-(3-Cl-pyridinyl) 217-218 828 Me H 2-Cl-4-F F2-(3-Cl-pyridinyl) 207-208 829 Me Me 2-Cl-4-F F 2-(3-Cl-pyridinyl)221-222 830 i-Pr H 2-C-4-F F 2-(3-Cl-pyridinyl) 166-167 831 H H 2-Cl-4-FF 2-(3-Cl-pyridinyl) 133-134 832 Me H 2-F-4-I Br 2-(3-Cl-pyridinyl)216-217 833 Me Me 2-F-4-I Br 2-(3-Cl-pyridinyl) 218-219 834 i-Pr H2-F-4-I Br 2-(3-Cl-pyridinyl) 217-218 835 H H 2,4-di-F Br2-(3-Cl-pyridinyl) 178-179 836 Me H 2-I, 4-F F 2-(3-Cl-pyridinyl)217-218 837 Me Me 2-I, 4-F F 2-(3-Cl-pyridinyl) 238-239 838 H H 2-Me,4-Cl CF₃ 2-(3-F-pyridinyl) * 839 Me H 2-Me, 4-Cl CF₃ 2-(3-F-pyridinyl) *840 Me Me 2-Me, 4-Cl CF₃ 2-(3-F-pyridinyl) * 841 i-Pr H 2-Me, 4-Cl CF₃2-(3-F-pyridinyl) * 842 H H 2,4-di-Cl CF₃ 2-(3-F-pyridinyl) * 843 Me Me2,4-di-Cl CF₃ 2-(3-F-pyridinyl) * 844 i-Pr H 2,4-di-Cl CF₃2-(3-F-pyridinyl) * 845 H H 2,4-di-Cl Br 2-(3-F-pyridinyl) * 846 Me H2,4-di-Cl Br 2-(3-F-pyridinyl) * 847 Me Me 2,4-di-Cl Br2-(3-F-pyridinyl) * 848 i-Pr H 2,4-di-Cl Br 2-(3-F-pyridinyl) * 849 H H2-Me, 4-Cl Br 2-(3-F-pyridinyl) * 850 Me H 2-Me, 4-Cl Br2-(3-F-pyridinyl) * 851 Me Me 2-Me, 4-Cl Br 2-(3-F-pyridinyl) * 852 i-PrH 2-Me, 4-Cl Br 2-(3-F-pyridinyl) * 853 Me H 2,4-di-Cl CF₃5-(1-CH₂CF₃-4-Cl- 181-183 pyrazolyl)

[0303] INDEX TABLE B Compound ¹H NMR Data (CDCl₃ solution unlessindicated otherwise)^(a) 185 (DMSO-d₆) δ 1.03(d, 6H), 2.18(s, 3H),3.92(m, 1H), 7.22-7.30(m, 2H), 7.35(m, 1H), 7.62(dd, 1H), 7.81(s, 1H),8.02(d, 1H), 8.15(dd, 1H), 8.55 (dd, 1H), 10.34(s, 1H). 217 (DMSO-d₆) δ1.01(d, 6H), 2.16(s, 3H), 3.92(m, 1H), 7.27(m, 2H), 7.35 (m, 1H),7.89(s, 1H), 7.96(m, 1H), 8.37(s, 2H), 10.42(s, 1H). 241 (DMSO-d₆) δ1.04(d, 6H), 4.0(m, 1H), 7.4(m, 2H), 7.5(m, 1H), 7.6(m 1H), 7.78(d, 2H),8.0(d, 2H), 8.2(d, 1H), 10.7(bs, 1H). 242 (DMSO-d₆) δ 1.16(d, 6H),4.1(m, 1H), 5.9(d, 1H), 7.1(m, 1H), 7.2(m, 3H), 7.69(s, 1H), 7.73(s,1H), 10.45(s, 1H). 243 (DMSO-d₆) δ 1.0(d, 6H), 3.9(m, 1H), 7.4(m, 2H),7.6(m, 1H), 7.8(m, 2H), 8.0(d, 1H), 8.1(d, 1H), 8.3(s, 1H), 10.6(s, 1H).244 (DMSO-d₆) δ 1.0(d, 6H), 4.0(m, 1H), 7.1(m, 1H), 7.43(m, 2H), 7.5(m,4H), 7.66(m, 2H), 10.6(s, 1H). 247 (DMSO-d₆) δ 1.02(d, 6H), 2.18(s, 3H),3.9-4.0(m, 1H), 7.2(m, 1H), 7.4(m, 1H), 7.8-7.9(m, 2H), 8.0(d, 2H),8.3(s, 1H), 10.3(s, 1H). 248 (DMSO-d₆) δ 1.02(d, 6H), 2.18(s, 3H),3.9-4.0(m, 1H), 7.2(m, 1H), 7.4(m, 1H), 7.8-7.9(m, 2H), 8.0(d, 2H),8.3(s, 1H), 10.3(s, 1H). 249 (DMSO-d₆) δ 1.04(d, 6H), 4.0(m, 1H), 7.4(m,2H), 7.76(s, 1H), 7.7(m, 1H), 7.74(m, 1H), 7.9(m, 1H), 7.97(d, 1H),8.07(s, 1H), 8.2(m, 1H), 10.7(bs, 1H). 264 (DMSO-d₆) δ 1.0(d, 6H),2.01(s, 3H), 2.17(s, 3H), 3.9(m, 1H), 7.3(m, 2H), 7.3-7.4(m, 1H),7.8-7.9(s, 1H), 7.9-8.0(m, 2H), 8.1-8.2(s, 1H), 10.3-10.4(s, 1H). 273(DMSO-d₆) δ 1.21(d, 6H), 2.24(s, 3H), 4.1-4.3(m, 1H), 5.9(d, 1H),7.02(d, 1H), 7.1-7.6(m, 7H), 7.78(s, 1H), 10.0(br s, 1H) 274 (DMSO-d₆) δ1.03(d, 6H), 1.94(s, 3H), 2.14(s, 3H), 3.9-4.0(m, 1H), 7.1-7.4(m, 8H),7.8(s, 1H), 7.9-8.0(d, 1H), 10.0(s, 1H). 275 (DMSO-d₆) δ 1.04(d, 6H),2.18(s, 3H), 3.9-4.0(m, 1H), 7.2-7.4(m, 6H), 7.4-7.6(m, 2H), 7.9(s, 1H),7.9-8.0(d, 1H), 10.1(br s, 1H). 278 δ 1.20(d, 6H), 2.19(s, 3H), 4.2(m,1H), 5.9-6.0(d, 1H), 7.1-7.5(m, 8H), 10.4-10.5(s, 1H). 314 (DMSO-d₆) δ1.03(d, 6H), 2.18(s, 3H), 3.31(s, 3H), 3.9-4.0(m, 1H), 7.2-7.3(m, 2H),7.3-7.4(m, 1H), 7.81(s, 1H), 7.9(d, 1H), 8.0(br d, 1H), 8.1(dd, 1H),8.3(d, 1H), 10.3(s, 1H). 398 δ 2.57(t, 2H), 3.57(q, 2H), 6.25(t, 1H),7.18-7.53(m, 8H), 9.17(s, 1H) 399 δ 1.23(d, 6H), 4.13(m, 1H), 5.92(d,1H), 7.35(m, 1H), 7.39(s, 1H) 7.42(m, 2H), 7.92(d, 1H), 8.51(d, 1H),10.23(br s, 1H). 402 δ 1.13(d, 6H), 4.15(m, 1H), 5.99(d, 1H), 7.40(m,1H), 7.41(m, 1H), 7.63(m, 1H), 7.80(s, 1H), 7.90(d, 1H), 8.48(d, 1H),10.2(br s, 1H). 562 δ 1.22(d, 6H), 2.18(s, 3H), 4.15(m, 1H), 4.37(s,1H), 5.91(d, 1H), 7.20(m, 4H), 7.30(m, 1H), 7.40(m, 1H), 7.52(m, 2H),7.96(s, 1H), 10.23(s, 1H). 563 (DMSO-d₆) δ 1.05(d, 6H), 2.15(s, 3H),3.74(s, 2H), 3.93(m, 1H), 7.26-7.70(m, 8H), 8.05(s, 1H), 8.35(br s, 2H),10.45(s, 1H). 572 δ 1.20(d, 6H), 2.01(s, 3H), 2.72(d, 3H), 4.13(m, 1H),6.01(d, 1H), 6.45 (s, 1H), 7.17(m, 5H), 7.51(m, 2H), 7.63(m, 1H),10.41(s, 1H). 586 (DMSO-d₆) δ 1.04(d, 6H), 2.32(s, 3H), 3.91(m, 1H),7.44-7.64(m, 4H), 7.77(s, 1H), 8.07(d, 1H), 8.27(d, 1H), 8.42(d, 1H),10.6(s, 1H). 590 (DMSO-d₆) δ 1.03(d, 6H), 3.88(m, 1H), 7.65(dd, 1H),7.88(s, 1H), 8.18(s, 1H), 8.22(d, 1H), 8.48-8.57(m, 3H), 10.95(s, 1H).592 δ 1.24(d, 6H), 4.22(m, 1H), 5.98(br d, 1H), 7.30-7.55(m, 6H),7.78(d, 1H), 7.99(d, 1H), 11.15(s, 1H). 603 δ 2.16(s, 3H),7.1-7.3(obscured, 1H), 7.40(d, 1H), 7.47(dd, 1H), 7.93(dd, 1H), 8.03(d,1H), 8.5(dd, 1H). 610 (DMSO-d₆) δ 1.04(m, 6H), 4.08(s, 3H), 8.18(m, 2H),8.22(d, 1H), 8.47(dd, 1H), 8.58(d, 1H), 9.17(d, 1H), 9.39(d, 1H),11.48(s, 1H). 611 (DMSO-d₆) δ 1.04(m, 6H), 2.50(s, 3H), 4.09(s, 3H),8.12(d, 1H), 8.17(s, 1H), 8.34(d, 1H), 8.37-8.52(m, 2H), 9.15(d, 1H),9.37(d, 1H), 11.11(s, 1H). 638 δ 1.30(t, 3H), 2.32(s, 3H), 3.55(q, 2H),6.23(br t, 1H), 7.30(s, 1H), 7.42(dd, 1H), 7.91(d, 1H), 8.20(apparent s,2H), 8.52(d, 1H), 10.92(s, 1H). 639 δ 2.21(s, 3H), 2.90(s, 3H), 3.12(s,3H), 7.42(m, 2H), 7.92(d, 1H), 7.92(d, 1H), 8.00(d, 1H), 8.50(d, 1H),9.92(br s, 1H). 640 δ 2.32(s, 3H), 4.02(t, 2H), 5.18-5.30(m, 2H),5.82-5.98(m, 1H), 7.37(s, 1H), 7.43(dd, 1H), 7.50(br t, 1H), 7.92(d,1H), 8.17(s, 1H), 8.37(d, 1H), 8.52(d, 1H), 11.12(br s, 1H). 641 δ0.91(t, 3H), 1.63(m, 2H), 2.31(s, 3H), 3.40(q, 2H), 6.83(br t, 1H),7.35(s, 1H), 7.42(dd, 1H), 7.91(d, 1H), 8.17(d, 1H), 8.24(d, 1H),8.52(d, 1H), 11.03(s, 1H). 642 δ 1.38(d, 3H), 2.14(s, 3H), 2.35(s, 3H),2.72(m, 2H), 4.38(m, 1H), 6.93(br d, 1H), 7.33(s, 1H), 7.43(dd, 1H),7.91(d, 1H), 8.18(d, 1H), 8.28(d, 1H), 8.52(d, 1H), 10.93(s, 1H). 643(DMSO-d₆) δ 2.32(s, 3H), 2.70(s, 3H), 7.63(m, 2H), 7.78(br s, 1H),8.18(br s, 1H), 8.21(d, 1H), 8.27(br s, 1H), 8.58(m, 2H). 644 (DMSO-d₆)δ 1.25(s, 9H), 2.31(s, 3H), 7.64(dd, 1H), 7.79(s, 1H), 8.03(br s, 2H),8.22(d, 1H), 8.28(s, 1H), 8.54(d, 1H), 10.62(s, 1H). 654 δ 2.33(s, 3H),2.75(br s, 6H), 6.9(br s, 1H), 7.33(s, 1H), 7.43(dd, 1H), 7.91(d, 1H),8.19(br s, 1H), 8.23(s, 1H), 8.50(d, 1H), 10.70(br s, 1H). 735 δ 1.39(d,6H), 2.81(d, 3H), 4.95(m, 1H), 6.59(s, 1H), 6.62(q, 1H), 7.12(s, 1H),7.24(s, 1H), 7.26(t, 1H), 7.80(d, 1H), 8.40(d, 1H), 9.56(br s, 1H). 772δ 1.24(d, 6H), 2.22(s, 3H), 4.20(m, 1H), 6.10(d, 1H), 7.35(s, 1H),7.44(t, 1H), 7.55(s, 2H), 7.87(s, 1H), 8.48(d, 1H), 10.7(s, 1H). 780 δ2.91(d, 3H), 6.3(m, 1H), 6.77(d, 1H), 7.3(obscured, 1H), 7.3-7.4(m, 2H),7.8-7.9(d, 1H), 8.5(d, 1H), 9.6-9.7(br s, 1H). 802 (DMSO-d₆) δ 7.1(d,1H), 7.5-7.7(m, 3H), 7.8(m, 2H), 8.1-8.2(d, 1H), 8.5(d, 1H), 10.5(br s,1H). 803 (DMSO-d₆) δ 1.03(d, 6H), 3.9(m, 1H), 7.1(d, 1H), 7.4-7.5(d,1H), 7.6(dd, 1H), 7.8(d, 1H), 8.2(d, 1H), 8.2(m, 1H), 8.5(d, 1H),10.5(br s, 1H). 804 δ 2.78(s, 3H), 3.04(s, 3H), 6.9(d, 1H), 7.1(d, 1H),7.29(d, 1H), 7.3-7.4 (dd, 1H), 7.8-7.9(d, 1H), 8.5(d, 1H), 9.8(br s,1H). 805 δ 2.18(s, 3H), 5.7(br s, 1H), 6.2(br s, 1H), 6.7(d, 1H), 7.3(m,1H), 7.3-7.4 (dd, 1H), 7.8-7.9(d, 1H), 8.4-8.5(d, 1H), 10.0(br s, 1H).806 δ 1.23(d, 6H), 2.19(s, 3H), 4.2(m, 1H), 5.9(br s, 1H), 6.7(d, 1H),7.21(d, 1H), 7.26(obscured, 1H), 7.3-7.4(dd, 1H), 7.8-7.9(d, 1H),8.4-8.5(d, 1H), 10.1(br s, 1H). 807 δ 2.20(s, 3H), 2.96(d, 3H), 6.1(brs, 1H), 6.65(d, 1H), 7.2(d, 1H), 7.26(obscured, 1H), 7.3-7.4(dd, 1H),7.8-7.9(d, 1H), 8.4-8.5(d, 1H), 10.1(br s, 1H). 808 δ 2.06(s, 3H),2.78(s, 3H), 3.08(s, 3H), 6.9(d, 1H), 7.0(s, 1H), 7.1(s, 1H),7.3-7.4(dd, 1H), 7.8-7.9(d, 1H), 8.4-8.5(d, 1H), 9.7-9.8(br s, 1H). 814(DMSO-d₆) δ 2.65(d, 3H), 7.52(d, 1H), 7.6-7.8(m, 2H), 7.9(d, 1H),8.0-8.1(t, 1H), 8.3-8.4(m, 1H), 8.4(d, 1H), 10.7(br s, 1H). 838(DMSO-d₆) δ 2.18(s, 3H), 7.41(d, 1H), 7.5(m, 2H), 7.67(s, 1H), 7.7 (m,1H), 7.8(s, 1H), 8.0-8.1(t, 1H), 8.4(d, 1H), 10.4-10.5(br s, 1H). 839(DMSO-d₆) δ 2.18(s, 3H), 2.66(d, 3H), 7.35(d, 1H), 7.49(d, 1H), 7.69 (s,1H), 7.7-7.8(m, 1H), 8.0-8.1(t, 1H), 8.3(m, 1H), 8.4(d, 1H), 10.4-10.5(br s, 1H). 840 δ 2.00(s, 3H), 2.75(s, 3H), 3.09(s,3H), 6.99(d, 1H),7.03(s, 1H), 7.4-7.5 (m, 1H), 7.5-7.6(t, 1H), 7.76(d, 1H), 8.4(d, 1H),10.4-10.5(br s, 1H). 841 (DMSO-d₆) δ 1.02(d, 6H), 2.19(s, 3H), 3.9(m,1H), 7.30(s, 1H), 7.48 (d, 1H), 7.6-7.8(m, 2H), 8.0(t, 1H), 8.1(d, 1H),8.4(d, 1H), 10.4(br s, 1H). 842 (DMSO-d₆) δ 7.56(d, 1H), 7.6(s, 1H),7.7-7.8(m, 2H), 7.9(m, 2H), 8.0-8.1(t, 1H), 8.4(d, 1H), 10.6-10.7(br s,1H). 843 δ 2.79(s, 3H), 3.08(s, 3H), 7.09(d, 1H), 7.25(d, 1H),7.4-7.5(m, 1H), 7.5-7.6(t, 1H), 7.78(s, 1H), 8.4(d, 1H), 10.5(br s, 1H).844 (DMSO-d₆) δ 1.01(d, 6H), 3.9(m, 1H), 7.46(d, 1H), 7.7(m, 1H), 7.8(s,1H), 7.85(d, 1H), 8.0(t, 1H), 8.2-8.3(d, 1H), 8.4(d, 1H), 10.6-10.7(brs, 1H). 845 (DMSO-d₆) δ 7.39(s, 1H), 7.55(d, 1H), 7.4(s, 1H), 7.4-7.5(m,1H), 7.8 (s, 1H), 7.85(d, 1H), 8.0(t, 1H), 8.4(d, 1H), 10.5(br s, 1H).846 (DMSO-d₆) δ 2.66(d, 3H), 7.40(s, 1H), 7.51(d, 1H), 7.6-7.7(m, 1H),7.84(d, 1H), 8.0(t, 1H), 8.3-8.4(m, 1H), 8.4(d, 1H), 10.5-10.6(br s,1H). 847 δ 2.80(s, 3H), 3.07(s, 3H), 7.10(s, 1H), 7.31(d, 1H), 7.35(s,1H), 7.4 (m, 1H), 7.5-7.6(t, 1H), 8.4(d, 1H), 9.5(br s, 1H). 848(DMSO-d₆) δ 1.02(d, 6H), 3.9(m, 1H), 7.45(apparent s, 2H), 7.6-7.7 (m,1H), 7.84(d, 1H), 7.9-8.0(t, 1H), 8.2(d, 1H), 8.36(d, 1H), 10.5(br s,1H). 849 (DMSO-d₆) δ 2.17(s, 3H), 7.33(s, 1H), 7.4(d, 1H), 7.5(m, 2H),7.6-7.7 (m, 1H), 7.9(s, 1H), 8.0(t, 1H), 8.4(d, 1H), 10.3(br s, 1H). 850(DMSO-d₆) δ 2.17(s, 3H), 2.67(d, 3H), 7.3-7.4(m, 2H), 7.5(d, 1H),7.6-7.7(m, 1H), 8.0(t, 1H), 8.2-8.3(m, 1H), 8.4(d, 1H), 10.3(br s, 1H).851 δ 2.08(s, 3H), 2.79(s, 3H), 3.09(s, 3H), 6.99(d, 1H), 7.11(s, 1H),7.28 (d, 1H), 7.4(m, 1H), 7.5-7.6(t, 1H), 8.3-8.4(d, 1H), 9.8(br s, 1H).852 (DMSO-d₆) δ 1.03(d, 6H), 2.17(s, 3H), 3.9(m, 1H), 7.3(d, 1H), 7.37(s, 1H), 7.5(d, 1H), 7.6-7.7(m, 1H), 7.9-8.0(t, 1H), 8.1(d, 1H), 8.3-8.4(d, 1H), 10.2-10.3(br s, 1H).

BIOLOGICAL EXAMPLES OF THE INVENTION Test A

[0304] Cotton seeds coated with a composition of Compound 208 from theNominal 1%, Nominal 2% and Nominal 3% concentration batches prepared asdescribed in Example E and untreated seeds for comparison were plantedin pots using sterile Sassafras soil and grown in a growth chamber with16 hours of light at 28° C. and 8 hours of darkness at 24° C. and 50%relative humidity. After 31 days two plants, each having true leaves,were selected from each of the seed batches and their cotyledons wereremoved. Adult Bemisia argentifolii (silverleaf whitefly) were added foregg-laying on the plants, and plastic cylinders capped with tissue paperwere fitted into the pots. Three days later, the adults were removed andthe leaves were checked to verify egg deposits. Fifteen days later(about six days after egg hatching), the infested leaves were removedfrom the plants and the 49-day results determined by counting the deadand live nymphs on the undersides of the leaves. Adult Bemisiaargentifolii were reintroduced for a second round of egg-laying on upperleaves of the plants, and plastic cylinders with tissue paper werefitted into the pots as before. Three days later, the adults wereremoved and the leaves were checked to verify egg deposits. Fourteendays later (about six days after egg hatching), the leaves were removedfrom the plants and the 66-day results determined by counting the deadand live nymphs on the undersides of the leaves. The results from bothrating times are summarized in Table A. TABLE A Control of SilverleafWhitefly by Coating Cottonseed with Compositions of Compound 208Treatment 49-day % Mortality 66-day % Mortality Nominal 1% concentration38 17 Nominal 2% concentration 72 41 Nominal 3% concentration 95 81Untreated 15 10

[0305] This test demonstrates that seed coatings according to thisinvention can protect cotton plants from the homopteran pest Bemisiaargentifolii for more than 9 weeks after seeding.

Test B

[0306] Cotton seeds coated with a composition of Compound 208 from theNominal 1%, Nominal 2% and Nominal 3% concentration batches prepared asdescribed in Example E and untreated seeds for comparison were plantedin 10-cm pots using sterile sassafras soil and grown in a growth chamberwith 16 hours of light and 8 hours of darkness at 25° C. and 50%relative humidity. Leaves were harvested from some of the plants 14 daysafter seeding, cut into 3 to 4 pieces, and placed one piece per well incovered 16-well translucent plastic trays in the growth chamber.Second-instar larvae of Heliothis virescens (tobacco budworm) were addedto the leaf pieces (1 larva/well, 6-10 larvae per treatment/leaf type),and the insect mortality was determined 48 hours and 96 hours afterinfestation. Leaves were harvested from other of the plants 64 daysafter seeding, cut into 3 to 4 pieces, and placed one piece per well incovered 16-well translucent plastic trays in the growth chamber.Second-instar larvae of Heliothis virescens (tobacco budworm) were addedto the leaf pieces (1 larva/well, 6-16 larvae per treatment/leaflocation), and the insect mortality was determined 72 hours and 96 hoursafter infestation. The results are summarized in Tables B1 and B2. TABLEB1 Control of Tobacco Budworm 14 Days after Seeding by CoatingCottonseed with Compositions of Compound 208 Treatment Leaf Type 48-hour% Mortality 96-hour % Mortality Nominal 1% True 0 33 concentrationCotyledon 10 70 Nominal 2% True 17 33 concentration Cotyledon 30 100Nominal 3% True 17 83 concentration Cotyledon 50 100 Untreated True 0 0Check Cotyledon 0 0

[0307] TABLE B2 Control of Tobacco Budworm 64 Days after Seeding byCoating Cottonseed with Compositions of Compound 208 72-hour 96-hourTreatment Leaf Location* % Mortality % Mortality Nominal 1% Top 25 93concentration Bottom 31 100 Nominal 2% Top 6 81 concentration Bottom 31100 Nominal 3% Top 75 100 concentration Bottom 50 100 Untreated Top 1212 Check Bottom 19 19

[0308] This test demonstrates that seed coatings according to thisinvention can protect cotton plants from the lepidopteran pest Heliothisvirescens for more than 9 weeks after seeding.

Test C

[0309] Cotton seeds treated with Compound 208 as prepared in Example E(Nominal 3% batch) and Compound 276, 486 and 502 as prepared in ExampleG and untreated seeds for comparison were planted in pots using eithersterile Sassafras soil or Drummer soil. Plants were grown in thegreenhouse and sampled when they started to produce buds (squares). Theleaves from the second node and the terminal leaves greater than 15 cm²were sampled (plants had approximately 5 leaves). The clipped leaf fromeach plant was cut into 4 pieces and each piece was placed into a wellwith one second-instar larvae of Heliothis virescens (tobacco budworm).Larval mortality was recorded 96 hours after sampling. TABLE C LarvalMortality from Feeding on Leaves with Seed Treatments Grown in Two SoilTypes 96-hour % Larval Mortality Compound Soil Type Terminal Leaf Baseof Plant 208 Sassafras 35.0 47.5 Drummer 58.3 79.2 276 Sassafras 81.381.3 Drummer 85.7 96.4 486 Sassafras 43.8 34.4 Drummer 57.1 67.9 502Sassafras 25.0 46.9 Drummer 87.5 75.0 Untreated Sassafras 9.4 6.3Drummer 16.7 4.2

Test D

[0310] Corn seeds treated with compounds 208, 484, 486, 502, 509 and 515as prepared in Example F were planted in pots with Sassafras soil.Plants were grown to whorl height (9th leaf) in the greenhouse andinfested with 25 fall armyworm (first-instar larvae) down the whorl. Sixdays after infesting the plant damage associated with the feeding wasrecorded. Plant damage was rated on a of 0 -100% (0 means no feeding).TABLE D Percent Plant Damage from Larval Feeding on Corn Plants withDifferent Seed Treatments Compound Percent Plant Damage 208 8 484 29 48623 509 10 502 10 515 7 Untreated 56

Test E

[0311] Corn seeds treated with Compound 502 as prepared in Example H atfive rates (Nominal 1.75%, 1.09%, 0.58%, 0.29% and 0.15%) were plantedin agricultural fileds near Newark, Del. and Donna Tex. When the plantshad produced a 5th leaf at least 10 cm long it was cut. One clipped leaffrom at least 16 plants for each rate was taken and placed into a wellwith one second-instar fall armyworm larvae. Larval mortality wasrecorded 72 hours after infesting.

[0312] Corn plants at the Donna site were measured to determine plantgrowth. Leaves were folded up into a tube, and the height from theground to the furthest leaf tip in the tube was recorded. TABLE E1Larval Mortality from Feeding on the 5th Leaf of Corn with Compound 502Seed Treatments Percent Mortality at 72 Hr Rate Newark Donna 1.75% 100.058.1 1.09% 100.0 71.0 0.58% 95.8 54.8 0.29% 87.5 35.5 0.15% 87.5 29.0Untreated 0.0 0.0

[0313] TABLE E2 Plant Height of Corn with Compound 502 Seed Treatmentsat Donna, TX Seed Treatment (Nominal rate) Untreated 0.15% 0.29% 0.58%1.09% 1.75% Height 41.64 40.76 42.36 44.28 45.32 48.32 (inches)

[0314] As can be seen from Table E2, treatment with Compound 502 appearsto have promoted plant growth in this test.

What is claimed is:
 1. A method for protecting from a propagule or aplant grown therefrom from an invertebrate pest, comprising: contactingthe propagule or the locus of the propagule with a biologicallyeffective amount of a compound of Formula I, an N-oxide thereof or anagriculturally suitable salt thereof

wherein A and B are independently O or S; R¹ is H, C₁-C₆ alkyl, C₂-C₆alkoxycarbonyl or C₂-C₆ alkylcarbonyl; R² is H or C₁-C₆ alkyl; R³ is H;C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ allynyl, or C₃-C₆ cycloalkyl, eachoptionally substituted with one or more substituents selected from thegroup consisting of halogen, CN, NO₂, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, Cl-C₄alkylsulfonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylcarbonyl, C₃-C₆trialkylsilyl, phenyl, phenoxy, 5-membered heteroaromatic rings, and6-membered heteroaromatic rings; each phenyl, phenoxy, 5-memberedheteroaromatic ring, and 6-membered heteroaromatic ring optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₆cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino,C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₄-C₈(alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆ alkoxycarbonyl,C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl and C₃-C₆trialkylsilyl; C₁-C₄ alkoxy; C₁-C₄ alkylamino; C₂-C₈ dialkylamino; C₃-C₆cycloalkylamino; C₂-C₆ alkoxycarbonyl or C₂-C₆ alkylcarbonyl; R⁴ is H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆haloalkyl, CN, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or NO₂; R⁵ is H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₄ alkoxyalkyl, C₁-C₄ hydroxyalkyl,C(O)R¹⁰, CO₂R¹⁰, C(O)NR¹⁰R¹¹, halogen, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,NR¹⁰R¹¹, N(R¹¹)C(O)R¹⁰, N(R¹¹)CO₂R¹⁰ or S(O)_(n)R¹²; R⁶ is H, C₁-C₆alkyl, C₁-C₆ haloalkyl, halogen, CN, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;R⁷ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₁-C₆haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl or C₃-C₆ halocycloalkyl;or R⁷ is a phenyl ring, a benzyl ring, a 5- or 6-membered heteroaromaticring, a naphthyl ring system or an aromatic 8-, 9- or 10-membered fusedheterobicyclic ring system, each ring or ring system optionallysubstituted with one to three substituents independently selected fromR⁹; R⁸ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, halogen, C₁-C₄ alkoxy orC₁-C₄ haloalkoxy; each R⁹ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy,C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆cycloalkylamino, C₄-C₈ (alkyl)(cycloalkyl)amino, C₂-C₄ alkylcarbonyl,C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; R¹⁰ is H, C₁-C₄ alkyl orC₁-C₄ haloalkyl; R¹¹ is H or C₁-C₄ alkyl; R¹² is C₁-C₄ alkyl or C₁-C₄haloalkyl; and n is 0, 1 or2.
 2. The method of claim 1 wherein A and Bare both O; R⁷ is a phenyl ring or a 5- or 6-membered heteroaromaticring selected from the group consisting of

each ring optionally substituted with one to three substituentsindependently selected from R⁹; Q is O, S, NH or NR⁹; W, X, Y and Z areindependendy N, CH or CR⁹, provided that in J-3 and J-4 at least one ofW, X, Y or Z is N.
 3. The method of claim 2 wherein R¹, R² and R⁸ areall H; R³ is C₁-C₄ alkyl optionally substituted with halogen, CN, OCH₃or S(O)_(p)CH₃; R⁴ group is attached at position 2; R⁴ is CH₃, CF₃,OCF₃, OCHF₂, CN or halogen; R⁵ is H, CH₃ or halogen; R⁶ is CH₃, CF₃ orhalogen; R⁷ is phenyl or 2-pyridinyl, each optionally substituted; and pis 0, 1 or
 2. 4. The method of claim 3 wherein R³ is C₁-C₄ alkyl and R⁶is CF₃.
 5. The method of claim 3 wherein R³ is C ₁-C₄ alkyl and R⁶ is Clor Br.
 6. A propagule contacted with a biologically effective amount ofa compound of Formula I according to claim 1, an N-oxide thereof or anagriculturally suitable salt thereof.
 7. The propagule according toclaim 6 which is a seed.
 8. The propagule of claim 7 which is a seed ofwheat, durum wheat, barley, oat, rye, maize, sorghum, rice, wild rice,cotton, flax, sunflower, soybean, garden bean, lima bean, broad bean,garden pea, peanut, alfalfa, beet, garden lettuce, rapeseed, cole crop,turnip, leaf mustard, black mustard, tomato, potato, pepper, eggplant,tobacco, cucumber, muskmelon, watermelon, squash, carrot, zinnia,cosmos, chrysanthemum, sweet scabious, snapdragon, gerbera,babys-breath, statice, blazing star, lisianthus, yarrow, marigold,pansy, impatiens, petunia, geranium or coleus.
 9. The propagule of claim8 which is a seed of cotton, maize, soybean or rice.
 10. The propaguleof claim 6 which is a rhizome, tuber, bulb or corm, or viable divisionthereof.
 11. The propagule of claim 10 which is a rhizome, tuber, bulbor corm, or viable division thereof, of potato, sweet potato, yam,garden onion, tulip, gladiolus, lily, narcissus, dahlia, iris, crocus,anemone, hyacinth, grape-hyacinth, freesia, ornamental onion,wood-sorrel, squill, cyclamen, glory-of-the-snow, striped squill, callalily, gloxinia or tuberous begonia.
 12. The propagule of claim 11 whichis a rhizome, tuber, bulb or corm, or viable division thereof, ofpotato, sweet potato, garden onion, tulip, daffodil, crocus or hyacinth.13. The propagule of claim 6 which is a stem or leaf cutting.
 14. Thepropagule of claim 6 coated with a composition comprising (1) abiologically effective amount of a compound of Formula I, an N-oxidethereof or an agriculturally suitable salt thereof, and (2) a filmformer or adhesive agent.
 15. A propagule comprising a biologicallyeffective amount of a compound of Formula I according to claim 1, anN-oxide thereof or an agriculturally suitable salt thereof.
 16. Aninvertebrate pest control composition for coating a propagule, thecomposition comprising (1) a biologically effective amount of a compoundof Formula I according to claim 1, an N-oxide thereof or anagriculturally suitable salt thereof, and (2) a film former or adhesiveagent.
 17. The composition according to claim 16 wherein the film formeror adhesive agent is selected from the group consisting of polyvinylacetates, polyvinyl acetate copolymers, hydrolyzed polyvinyl acetates,polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohols,polyvinyl alcohol copolymers, polyvinyl methyl ether, polyvinyl methylether-maleic anhydride copolymer, waxes, latex polymers, cellulosesincluding ethylcelluloses and methylcelluloses, hydroxymethylcelluloses,hydroxypropylcellulose, hydroxymethylpropylcelluloses,polyvinylpyrrolidones, alginates, dextrins, malto-dextrns,polysaccharides, fats, oils, proteins, karaya gum, jaguar gum,tragacanth gum, polysaccharide gums, mucilage, gum arabics, shellacs,vinylidene chloride polymers and copolymers, lignosulfonates, acryliccopolymers, starches, polyvinylacrylates, zeins, gelatin,carboxymethylcellulose, chitosan, polyethylene oxide, acrylimidepolymers and copolymers, polyhydroxyethyl acrylate, methylacrylimidemonomers, alginate, ethylcellulose, polychloroprene and syrups ormixtures thereof.
 18. The composition according to claim 17 wherein thefilm former or adhesive agent is selected from polymers and copolymersof vinyl acetate, polyvinylpyrrolidone-vinyl acetate copolymer andwater-soluble waxes.
 19. The composition according to claim 16 fercomprising an effective amount of at least one additional biologicallyactive compound or agent.
 20. The composition according to claim 19wherein at least one additional biologically active compound or agent isselected from arthropodicides of the group consisting of pyrethroids,carbamates, neonicotinoids, neuronal sodium channel blockers,insecticidal macrocyclic lactones, yaminobutyric acid (GABA)antagonists, insecticidal ureas and juvenile hormone mimics.
 21. Thecomposition according to claim 19 wherein at least one additionalbiologically active compound or agent is selected from the groupconsisting of abamectin, acephate, acetamiprid, amidoflumet (S-1955),avermectin, azadirachtin, azinphos-methyl, bifenthrin, binfenazate,buprofezin, carbofuran, chlorfenapyr, chlorfluazuron, chlorpyrifos,chlorpyrifos-methyl, chromafenozide, clothianidin, cyfluthrin,beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, cypermethrin,cyromazine, deltamethrin, diafenthiuron, diazinon, diflubenzuron,dimethoate, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole,fenothicarb, fenoxycarb, fenpropathrin, fenproximate, fenvalerate,fipronil, flonicamid, flucythrinate, tau-fluvalinate, flufenerim(UR-50701), flufenoxuron, fonophos, halofenozide, hexaflumuron,imidacloprid, indoxacarb, isofenphos, lufenuron, malathion, metaldehyde,methamidophos, methidathion, methomyl, methoprene, methoxychlor,monocrotophos, methoxyfenozide, nithiazin, novaluron, noviflumuron(XDE-007), oxamyl, parathion, parathion-methyl, permethrin, phorate,phosalone, phosmet, phosphamidon, pirimicarb, profenofos, pymetrozine,pyridalyl, pyriproxyfen, rotenone, spinosad, spiromesifin (BSN 2060),sulprofos, tebufenozide, teflubenzuron, tefluthrin, terbufos,tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb,thiosultap-sodium, tralomethrin, trichlorfon and triflumuron, aldicarb,oxamyl, fenamiphos, amitraz, chinomethionat, chlorobenzilate, cyhexatin,dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide,fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben,tebufenpyrad; and biological agents such as Bacillus thuringiensisincluding ssp. aizawai and kurstaki, Bacillus thuringiensis deltaendotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.22. The composition according to claim 19 wherein at least oneadditional biologically active compound or agent is selected fromfungicides of the group consisting of acibenzolar, azoxystrobin,benomyl, blasticidin-S, Bordeaux mixture (tribasic copper sulfate),bromuconazole, carpropamid, captafol, captan, carbendazim, chloroneb,chlorothalonil, copper oxychloride, copper salts, cyflufenamid,cymoxanil, cyproconazole, cyprodinil,(S)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH 7281), diclocymet (S-2900), diclomezine, dicloran, difenoconazole,(S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one(RP 407213), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,dodine, edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid (SZX0722), fenpiclonil, fenpropidin,fenpropimorph, fentin acetate, fentin hydroxide, fluazinam, fludioxonil,flumetover (RPA 403397), flumorf/flumorlin (SYP-L190), fluoxastrobin(HEC 5725), fluquinconazole, flusilazole, flutolanil, flutriafol,folpet, fosetyl-aluminum, furalaxyl, furametapyr (S-82658),hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane,kasugamycin, kresoxim-methyl, mancozeb, maneb, mefenoxam, mepronil,metalaxyl, metconazole, metominostrobin/fenominostrobin (SSF-126),metrafenone (AC 375839), myclobutanil, neo-asozin (ferricmethanearsonate), nicobifen (BAS 510), orysastrobin, oxadixyl,penconazole, pencycuron, probenazole, prochloraz, propamocarb,propiconazole, proquinazid (DPX-KQ926), prothioconazole (JAU 6476),pyrifenox, pyraclostrobin, pyrimethanil, pyroquilon, quinoxyfen,spiroxamine, sulfur, tebuconazole, tetraconazole, thiabendazole,thiiluzamide, thiophanate-methyl, thiram, tiadinil, triadimefon,triadimenol tricyclazole, trifloxystrobin, triticonazole, validamycinand vinclozolin.
 23. The composition according to claim 19 wherein atleast one additional biologically active compound or agent is selectedfrom fungicides in the group consisting of thiram, maneb, mancozeb andcaptan.